Anti-inflammatory agents

ABSTRACT

Disclosed are novel compounds that are useful in regulating the expression of interleukin-6 (IL-6) and/or vascular cell adhesion molecule-1 (VCAM-1), and their use in the treatment and/or prevention of cardiovascular and inflammatory diseases and related disease states, such as, for example, atherosclerosis, asthma, arthritis, cancer, multiple sclerosis, psoriasis, and inflammatory bowel diseases, and autoimmune disease(s). Also, disclosed are compositions comprising the novel compounds, as well as methods for their preparation.

This is a continuation of application Ser. No. 13/257,802, which has a371(c) date of Nov. 1, 2011, and is a national stage entry under 35U.S.C. § 371 of PCT/IB2010/000826, filed on Mar. 16, 2010, which claimsthe benefit of U.S. Provisional Application No. 61/161,089, filed Mar.18, 2009, all of which are incorporated herein by reference.

The present invention relates to novel compounds that are useful inregulating the expression of interleukin-6 (IL-6) and/or vascular celladhesion molecule-1 (VCAM-1), and their use in the treatment and/orprevention of cardiovascular and inflammatory diseases and relateddisease states, such as, for example, atherosclerosis, asthma,arthritis, cancer, multiple sclerosis, psoriasis, and inflammatory boweldiseases, and autoimmune disease(s). The invention also includespharmaceutical compositions comprising the novel compounds, as well asmethods for their preparation.

Coronary heart disease (CHD) remains a leading cause of death inindustrialized nations. A primary cause of CHD is atherosclerosis, adisease characterized by the deposition of lipids in the arterial vesselwall, resulting in a narrowing of the vessel passages and, ultimatelyleading to hardening of the vascular system.

It is generally accepted that atherosclerosis can begin with localinjury to the arterial endothelium, followed by proliferation ofarterial smooth muscle cells from the medial layer to the intimal layer,along with the deposition of lipids and the accumulation of foam cellsin the lesion. As the atherosclerotic plaque develops, it progressivelyoccludes more of the affected blood vessel and can eventually lead toischemia or infarction. Thus, there is a continued effort to developtreatments to inhibit or prevent the progression of atherosclerosis inpatients in need thereof.

Cardiovascular disease has been linked to several causative factors,including hypercholesterolemia, hyperlipidemia, and the expression ofvascular cell adhesion molecule-1 (VCAM-1) in vascular endothelialcells. VCAM-1 promotes the adhesion of lymphocytes, monocytes,eosinophils, and basophils. Certain melanoma cells can use VCAM-1 toadhere to the endothelium, and VCAM-1 may participate in monocyterecruitment to atherosclerotic sites. As a result, VCAM-1 is of interestas a drug target.

The VCAM-1 gene is a member of the immunoglobulin (Ig) superfamily andencodes a cell-surface sialoglycoprotein expressed by cytokine-activatedendothelial cells. This type-1 membrane protein mediatesleukocyte-endothelial cell adhesion and signal transduction, and mayplay a role in the development of artherosclerosis and rheumatoidarthritis. VCAM-1, also known as CD106, has several roles in the immunesystem. The VCAM-1 protein contains six or seven immunoglobulin domains,and is expressed in both large and small vessels only after endothelialcells are stimulated by cytokines.

Adhesion of leukocytes to the endothelium represents a fundamental,early event in many inflammatory conditions, including atherosclerosis,autoimmune disorders, and bacterial and viral infections. Leukocyterecruitment to the endothelium begins when inducible adhesion moleculereceptors on the surface of endothelial cells interact with theircounter-receptors on immune cells. Vascular endothelial cells determinewhich type(s) of leukocyte(s) (e.g., monocytes, lymphocytes,neutrophils) are recruited, by selectively expressing specific adhesionmolecules, such as VCAM-1, intracellular adhesion molecule-1 (ICAM-1),and E-selectin.

In the early stage of the atherosclerotic lesion, there is localizedendothelial expression of VCAM-1 and selective recruitment ofmononuclear leukocytes that express the integrin counter-receptor VLA-4.Because of the selective expression of VLA-4 on monocytes andlymphocytes, but not neutrophils, VCAM-1 is important in mediating theselective adhesion of mononuclear leukocytes. Subsequent conversion ofleucocytes to foamy macrophages results in the synthesis of a widevariety of inflammatory cytokines, growth factors, and chemoattractantsthat help expand leukocyte and platelet recruitment, smooth muscle cellproliferation, endothelial cell activation, and the extracellular matrixsynthesis characteristic of maturing atherosclerotic plaques.

VCAM-1 is also a mediator in inflammatory diseases. For example, it isknown that the expression of VCAM-1 and ICAM-1 are increased inasthmatics (Pilewski et al. (1995) Am. J. Respir. Cell Mol. Biol. 12,1-3; Ohkawara et al. (1995) Am J. Respir. Cell Mol. Biol. 12, 4-12).Further examples of non-cardiovascular inflammatory diseases mediated byVCAM-1 include rheumatoid and osteoarthritis, asthma, dermatitis, andmultiple sclerosis. Blocking the integrin receptors for VCAM-1 andICAM-1 (VLA-4 and LFA-1, respectively) suppresses both early- andlate-phase responses in an ovalbumin-sensitized rat model of allergicairway responses (Rabb et al. (1994) Am. J. Respir. Care Med. 149,1186-1191). There is also increased expression of endothelial adhesionmolecules, including VCAM-1, in the microvasculature of rheumatoidsynovium (Koch et al. (1991) Lab. Invest. 64, 313-322; Morales-Ducret etal. (1992) Immunol. 149, 1421-31).

Neutralizing antibodies directed against VCAM-1 or its counter receptor,VLA-4, can delay the onset of diabetes in a mouse model (NOD mice),which spontaneously develop the disease (Yang et al. (1993) Proc. Natl.Acad. Sci. USA 90, 10494-10498; Burkly et al. (1994) Diabetes 43,523-534; Baron et al. (1994) J. Clin. Invest. 93, 1700-1708). Monoclonalantibodies to VCAM-1 can also have beneficial effects in animal modelsof allograft rejection, suggesting that inhibitors of VCAM-1 expressionmay also have utility in preventing transplant rejection (Oroez et al.(1992) Immunol. Lett. 32, 7-12).

VCAM-1 is expressed by cells in both a membrane-bound and soluble form.The soluble form has been shown to induce chemotaxis of vascularendothelial cells in vitro and to stimulate an angiogenic response inrat cornea (Koch et al. (1995) Nature 376, 517-519). Inhibitors of theexpression of soluble VCAM-1 have potential therapeutic value intreating diseases with an angiogenic component, including tumor growthand metastasis (Folkman & Shing (1992) Biol. Chem. 10931-10934).

Because cardiovascular and inflammatory diseases are currently a leadingcause of death and disability in the developed world, there is a strongneed to identify new methods and pharmaceutical agents for itstreatment. Thus, there is a need to identify and manipulate syntheticcompounds that can affect the expression of mediators of theinflammatory process, such as, for example, VCAM-1.

Interleukin-6 (IL-6) is a 22-27-kDa secreted glycoprotein that exhibitsgrowth stimulatory and pro-inflammatory activities. IL-6 has also beencalled interferon-β2 (IFN-β2), IL-1-inducible 26-kDa protein,hepatocyte-stimulating factor, cytotoxic T-cell differentiation factor,and B-cell stimulatory factor (Trikha et al. (2003) Clin. Cancer Res. 9,4653-4665). IL-6 was originally identified in monocytes/macrophages,fibroblasts, and endothelial cells.

IL-6 is secreted by various cell types and exerts its activities bybinding to a high-affinity receptor complex, consisting of two membraneglycoproteins, an 80-kDa component receptor that binds IL-6 with lowaffinity (IL-6R) and a signal-transducing component of 130 kDa (alsoknown as gp130) that does not bind IL-6 itself, but is required forhigh-affinity binding of IL-6 by the complex. The IL-6R can be cleavedby a transmembrane metalloproteinase to yield a soluble IL-6R.

IL-6 levels are rapidly elevated in the circulation in numerousinfectious, inflammatory, autoimmune diseases, and in some cancers, inassociation with increased synthesis of other cytokines, stimulated byinfection, trauma, and immunological challenge. (Trikha et al. (2003)Clin. Cancer Res. 9, 4653-4665). IL-6 has been implicated in variousdiseases and disorders, including multiple myeloma (Rossi et al. (2005)Bone Marrow Transplantation 36, 771-779), lymphomas (Emilie et al.(1994) Blood 84, 2472-2479), neurological disorders, such asneurodegeneration, astrocytosis, and cerebral angiogenesis (Campbell etal. (1993) Proc. Natl. Acad. Sci. USA 90, 10061-10065), autoimmunedisorders (e.g., rheumatoid arthritis), inflammatory diseases,Alzheimer's disease, myocardial infarction, Paget's disease,osteoporosis, solid tumors, prostate and bladder cancers (Trikha et al.(2003) Clin. Cancer Res. 9, 4653-4665), septic shock, transplants, acuteinfections of the central nervous system, cardiac myxoma (Wijdenes etal. (1991) Mol. Immunol. 28, 1183-1192), tumor-induced cachexia (Cahlinet al. (2000) Cancer Res. 60, 5488-5489), cancer-associated depression,and cerebral edema secondary to brain tumors (Musselman at al. (2001)Am. J. Psychiatry 158, 1252-1257). Inflammation and IL-6 are nowspecifically thought to be linked to heart attacks (Taubes (2002)Science 296, 242).

Generally, it is known that IL-6 is abnormally produced in someinflammatory, autoimmune, and neoplasmic diseases. It has been proposedthat abnormal production of IL-6 is an aspect of the mechanisms of thesediseases (Hirano et al. (1990) Immunol. Today, 11, 443-449; Sehgal(1990) Proc. Soc. Exp. Biol. Med. 195, 183-191; Grau (1990) Eur.Cytokine Net 1, 203-210; Bauer et al. (1991) Ann. Hematol. 62, 203-210;Campbell et al. (1991) J. Clin. Invest. 7, 739-742; Roodman et al.(1992) J. Clin. Invest. 89, 46-52). In particular, it is known that IL-6is associated with neuropathological processes, and its level in bloodis increased in diseases invading the central nervous system. It hasbeen found that IL-6 increases the level of tau epitope, by stimulatingthe dementia-associated phosphorylation of the tau protein in neuronalcells (Quintanilla et al. (2004) Exp. Cell Res. 295, 245-257). Micelacking IL-6 have enhanced resistance to glutamate toxicity andincreased viability of neuronal cells (Fisher et al. (2001) J.Neuroimmunol. 119, 1-9). It has also been found that IL-6 amplifies acalcium influx signal for the neurotransmitter N-methyl-D-aspartate(NMDA), through voltage-sensitive calcium channels, which provides someevidence that the increased IL-6 level may play a role in inducingpathological changes in central nervous system diseases (Qiu et al.(1998) 18,10445-10456). It has also been reported that the abnormalexpression of IL-6 is a pathogenic mechanism in other diseases,including cardiac myxoma, uterine cancer (Kishimoto et al. (1988) Ann.Rev. Immunol. 6, 485), multiple myeloma, histiocytomas (Taga et al.(1987) J. Exp. Med. 166, 967), plasmacytoma, hematological diseases,including plasma cell dyscrasias, leukemia, and lymphoma (Kishimoto(1989) Blood 74, 1; Taga et al. (1987) J. Exp. Med. 166, 967; Klein etal. (1991) Blood 78, 1198-1204), proliferative glomerulonephritis,activated multiclonal B-cell (types I-IV) allergic diseases, rheumatoidarthritis (Hirano et al. (1988) Eur. J. Immunol. 18, 1797), diabetes(Campbell et al. (1991) J. Clin. Invest. 87, 739-742), multiplesclerosis, Systemic Lupus Erythematosus, septic shock, bacterialinfections, viral infections, osteoporosis (Roodman et al. (1992) J.Clin. Invest. 89, 46-52; Jilka et al. (1992) Science 257, 88-91),chronic immunodeficiency syndrome and autoimmune immunodeficiencysyndromes, including AIDS (Med. Immunol. (1988) 15, 195-201), andinflammatory diseases, including inflammatory bowel diseases (such asCrohn's disease and ulcerative colitis) (WO99/47170). It is known thatIL-6 is associated with some central nervous system diseases (Frei etal. (1991) J. Neuroimmunol. 31, 147).

Interleukin-6 is secreted by many advanced cancers, such ashormone-independent prostate cancer, and is believed to be a growthfactor for such cancers. Additionally, the secretion of IL-6 by cancercells is believed to cause cachexia, the wasting syndrome characteristicof advanced cancers. Thus, reducing the level of IL-6 would be useful intreating such cancers. IL-6 also plays a key role in B cell development.Autoimmune diseases with a significant antibody component, such asrheumatoid arthritis, could be treated by decreasing IL-6 levels.Disorders involving B cell proliferation, such as multiple myeloma and Bcell lymphoma, could also be treated by reducing IL-6 activity.Additionally, IL-6 plays an important role in bone remodeling bypromoting bone resorption. Reducing IL-6 activity would have the effectof reducing bone resorption and could be used to treat osteoporosis.

Accordingly, there have been various attempts to reduce the levels ofIL-6, which are believed to be associated with the pathogenic mechanismsof these various diseases and conditions. A steroid formulation has beenused for suppressing the cytokines in the art, but such medicines maycauses severe side-effects, such as peptic ulcers, if administered foran extended period.

Anti-IL-6 antibodies have been shown to be effective in treating severaldiseases and disorders. For example, anti-IL-6 monoclonal antibodieshave been shown to block the proliferation of myeloma cells both in vivoand in vitro (Rossi et al. (2005) Bone Marrow Transplantation 36,771-779). Administration of anti-IL-6 antibodies to chronic rheumatoidarthritis patients was found to alleviate the symptoms of the disease(Wendling et al. (1993) J. Rheumatol. 20, 259-262). Anti-IL-6 antibodieshave also been shown to be effective in treating AIDS-associatedlymphoma (Emilie et al. (1994) Blood 84, 2472-2479), and metastaticrenal cell carcinoma (Blay et al. (1997) Int. J. Cancer 72, 424-430).Clinical results involving the administration of anti-IL-6 antibodies totreat various other diseases and disorders are summarized in Trikha etal. (2003) Clin. Cancer Res. 9, 4653-4665.

Thus, the present invention provides non-naturally occurring compoundsthat are useful for regulating the expression of interleukin-6 (IL-6)and vascular cell adhesion molecule-1 (VCAM-1), as well as the use ofsuch compounds for the treatment and prevention of cardiovascular andinflammatory diseases, such as, for example, atherosclerosis, asthma,arthritis, cancer, multiple sclerosis, psoriasis, inflammatory boweldiseases, and autoimmune disease(s).

Without wishing to be bound to theory, it is believed that the compoundsof the invention act by inhibiting expression of IL-6 and/or VCAM-1 inthe subject receiving the compound. However, regardless of the mechanismof action, administration of one or more compounds of the presentinvention will reduce the levels of IL-6 and/or VCAM-1 in the subjectand as a result treat or reduce the incidence of cardiovascular and/orinflammatory diseases.

One aspect of the invention provides a method for inhibiting theexpression of, or reducing IL-6 and/or VCAM-1 in a subject comprisingadministering to the subject in need thereof, a therapeuticallyeffective amount of at least one compound of Formula I:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, orhydrate thereof, wherein:

Q and V are independently selected from CH and nitrogen;

U is selected from C═O, C═S, SO₂, S═O, SR₁, CR₁R₂, CR₁OR₂, CR₁SR₂;

R₁ and R₂ are independently selected from hydrogen and C₁-C₆ alkyl;

Rc is selected from hydrogen, C₁-C₆ alkyl, and C₃-C₆ cycloalkyl;

Ra₁, Ra₂, and Ra₃ are independently selected from hydrogen, C₁-C₆ alkyl,C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₁-C₆ alkoxy, halogen, amino, amide,hydroxyl, heterocycle, and C₃-C₆ cycloalkyl, wherein Ra₁ and Ra₂ and/orRa₂ and Ra₃ may be connected to form a cycloalkyl or a heterocycle;

Rb₂ and Rb₆ are independently selected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆ alkenyl, C₃-C₆ cycloalkyl, hydroxyl, and amino;

Rb₃ and Rb₅ are independently selected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, hydroxyl, and amino, wherein

Rb₂ and Rb₃ and/or Rb₅ and Rb₆ may be connected to form a cycloalkyl ora heterocycle;

represents a 3-8 membered ring system wherein:

W is selected from carbon and nitrogen;

Z is selected from CR₆R₇, NR₈, oxygen, sulfur, —S(O)—, and —SO₂—; saidring system being optionally fused to another ring selected fromcycloakyl, heterocycle, and phenyl, and wherein said ring system isselected from, for example, rings having the structures

R₃, R₄, and R₅ are independently selected from hydrogen, C₁-C₆ alkyl,C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, aryl,aryloxy, hydroxyl, amino, amide, oxo, —CN, and sulfonamide;

R₆ and R₇ are independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₆alkenyl, C₁-C₆ alkynyl, C₃-C₆ cycloalkyl, aryl, halogen, hydroxyl, —CN,amino, sulfonyl, acyl, and amido;

R₈ is selected from hydrogen, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl,acyl, and C₃-C₆ cycloalkyl; and

R₉, R₁₀, R₁₁, and R₁₂ are independently selected from hydrogen, C₁-C₆alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₃-C₆ cycloalkyl, aryl,heterocycle, hydroxyl, sulfonyl, and acyl,

provided that

if Q=CH, then at least one of Ra₁, Ra₂, and Ra₃ is not hydrogen;

if Z═NAc, then only one of Ra₁, Ra₂, or Ra₃ is hydrogen, and Ra₁ is not—OCH₂CH₂OMe; and

if Ra₁ and Ra₃ are both OMe, then R₈ is not —C(O)CH₂OH.

In certain embodiments, the method for inhibiting the expression of, orreducing IL-6 and/or VCAM-1 in a subject, comprises administering atherapeutically effective amount of at least one compound of Formula II:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, orhydrate thereof, wherein:

Q and V are independently selected from CH and nitrogen;

U is selected from C═O, C═S, SO₂, S═O, SR₁, CR₁R₂, CR₁OR₂, and CR₁SR₂;

R₁ and R₂ are independently selected from hydrogen and C₁-C₆ alkyl;

Rc is selected from hydrogen, C₁-C₆ alkyl, and C₃-C₆ cycloalkyl;

Ra₁, Ra₂, and Ra₃ are independently selected from hydrogen, C₁-C₆ alkyl,C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, halogen,amino, amide, hydroxyl, cycloalkyl, and heterocycle, wherein Ra₁ and Ra₂and/or Ra₂ and Ra₃ may be connected to form a cycloalkyl or aheterocycle;

Rb₂ and Rb₆ are independently selected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆ alkenyl, C₃-C₆ cycloalkyl, hydroxyl, and amino;

Rb₃ and Rb₅ are independently selected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, hydroxyl, and amino, wherein

Rb₂ and Rb₃ and/or Rb₅ and Rb₆ may be connected to form a cycloalkyl ora heterocycle;

Rn₁ is selected from hydrogen, C₁-C₆ alkyl, and C₃-C₆ cycloalkyl; and

Rn₂ is selected from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocycle, aryl,alkenyl, sulfonyl, and acyl, wherein Rn₁ and/or Rn₂ may be connectedwith Rb₃ and/or Rb₅ to form a 5- or 6-membered heterocyclic ring,provided that

at least one of Ra₁, Ra₂, and Ra₃ are not hydrogen; and

Rn₁ and Rn₂ are not both methyl or ethyl.

In other embodiments, the method for inhibiting the expression of, orreducing IL-6 and/or VCAM-1 in a subject, comprises administering atherapeutically effective amount of at least one compound of FormulaIII:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, orhydrate thereof, wherein:

Q is selected from CR₁₂ and nitrogen;

V is selected from CH and nitrogen;

U is selected from C═O, C═S, SO₂, S═O, SR₁, CR₁R₂, CR₁OR₂, CR₁SR₂;

X is selected from oxygen, sulfur, SR₁, nitrogen, NR₆R₇, and CR₆R₇;

Z is selected from unsubstituted C₁-C₆ alkyl and C₁-C₆ alkyl substitutedwith one or more groups selected from C₁-C₃ alkyl, C₁-C₃ alkoxy,cyclopropyl, hydroxyl, amino, and halogen;

n is selected from 0, 1, 2, 3, 4, or 5;

G is selected from heterocycle, cycloalkyl, and aryl;

R₁ and R₂ are independently selected from hydrogen, and C₁-C₆ alkyl;

R₆, R₇, and R₁₂ are independently selected from hydrogen, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, heterocycle, C₁-C₆ alkoxy, and halogen;

Rc is selected from hydrogen, C₁-C₆ alkyl, and C₃-C₆ cycloalkyl;

Ra₁, Ra₂, and Ra₃ are independently selected from hydrogen, C₁-C₆ alkyl,C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, halogen,amino, amide, hydroxyl, and heterocycle, wherein Ra₁ and Ra₂ and/or Ra₂and Ra₃ may be connected to form a cycloalkyl or a heterocycle;

Rb₂ and Rb₆ are independently selected from hydrogen, halogen, C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkenyl, hydroxyl, and amino; and

Rb₃ and Rb₅ are independently selected from hydrogen, halogen, C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, hydroxyl, and amino, wherein

Rb₂ and Rb₃ and/or Rb₅ and Rb₆ may be connected to form a cycloalkyl ora heterocycle;

provided that

if Ra₁ and Ra₃ are OMe, and Q=CH, then

is not

at least one of Ra₁, Ra₂, and Ra₃ is not hydrogen; and

if Ra₂ or Ra₃ is chloro, then Ra₁ is not hydrogen.

In some embodiments, the method for inhibiting the expression of, orreducing IL-6 and/or VCAM-1 in a subject, comprises administering atherapeutically effective amount of at least one compound of Formula IV:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, orhydrate thereof, wherein:

Q₁ is selected from nitrogen and C—Ra₁;

Q₂ is selected from nitrogen and C—Ra₂;

Q₃ is selected from nitrogen and C—Ra₃;

V is selected from CH and nitrogen;

U is selected from C═O, C═S, SO₂, S═O, SR₁, CR₁R₂, CR₁OR₂, CR₁SR₂;

R₁ and R₂ are independently selected from hydrogen and C₁-C₆ alkyl;

Ra₂, and Ra₃ are independently selected from hydrogen, C₁-C₆ alkyl,C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, amino,amide, and heterocycle, wherein Ra₁ and Ra₂ and/or Ra₂ and Ra₃ may beconnected to form a cycloalkyl or a heterocycle;

Rb₂ and Rb₆ are independently selected from hydrogen, halogen, C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkenyl, hydroxyl, and amino; and

Rb₃ and Rb₅ are independently selected from hydrogen, methyl, ethyl,C₃-C₆ cycloalkyl, C₁-C₃ alkoxy, and amino, wherein

Rb₂ and Rb₃ and/or Rb₅ and Rb₆ may be connected to form a cycloalkyl ora heterocycle,

provided that

if Ra₃ is alkoxy, then Ra₁ is not hydrogen;

if Ra₂ is

then Rb₃ is not hydrogen; and

if Rb₂, Rb₅, and Rb₆ are hydrogen, then Rb₃ is not —CH₂OH.

In a further embodiment, the method for inhibiting the expression of, orreducing IL-6 and/or VCAM-1 in a subject, comprises administering atherapeutically effective amount of at least one compound of Formula V:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, orhydrate thereof, wherein:

Q is selected from CR₆ and nitrogen;

U is selected from C═O, C═S, SO₂, S═O, SR₁, CR₁R₂, CR₁OR₂, CR₁SR₂;

Y is selected from oxygen, nitrogen, sulfur, NR₆, CR₆R₇;

A is C₁-C₄ alkyl, wherein the alkyl chain may be connected to Y, D, Rb₃and/or R_(b5) to form a cycloalkyl or heterocycle;

D may be absent or present, and if present is selected from —OR₁,—NR₁R₂;

R₁ and R₂ are independently selected from hydrogen, C₁-C₆ alkyl, C₃-C₆cycloalkyl, sulfonamide, carboxamide, acyl, and nitrite, wherein R₁ andR₂ may be connected to form a cycloalkyl or a heterocycle;

R₆ and R₇ are independently selected from hydrogen, C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₁-C₆ alkoxy, hydroxyl, and halogen;

Ra₁, Ra₂, and Ra₃ are independently selected from hydrogen, C₁-C₆ alkyl,C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, halogen,amino, amide, hydroxyl, and heterocycle, wherein Ra₁ and Ra₂ and/or Ra₂and Ra₃ may be connected to form a cycloalkyl or a heterocycle;

Rb₂ and Rb₆ are independently selected from hydrogen, halogen, C₁-C₆alkyl, and C₃-C₆ cycloalkyl; and

Rb₃ is selected from hydrogen, halogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl,C₁-C₆ alkoxy, hydroxyl, and amino, wherein

Rb₂ and Rb₃ and/or Rb₅ and Rb₆ may be connected to form a cycloalkyl ora heterocycle,

provided that

at least one of Ra₁, Ra₂, and Ra₃ is not hydrogen; and

if Ra₁ and Ra₃ are both hydrogen, and Y=nitrogen, then Ra₂ is nothydrogen, —OAc, or —OMe.

The invention also provides pharmaceutical compositions comprising oneor more compounds of the invention, (i.e., compounds of Formula I,Formula II, Formula III, Formula IV, and Formula V, and stereoisomers,tautomers, pharmaceutically acceptable salts, and hydrates of compoundsof Formula I, II, III, IV, and V) together with at least onepharmaceutically acceptable carrier, adjuvant, and/or excipient. Inaddition, methods of preparing compounds of Formula I, Formula II,Formula III, Formula IV, and Formula V, and stereoisomers, tautomers,and pharmaceutically acceptable salts and hydrates thereof areencompassed by the invention.

The invention further provides methods of treatment and/or prevention ofcardiovascular and inflammatory diseases and related disease states byadministering to a subject in need thereof, a therapeutically effectiveamount of one or more compounds of Formula I, Formula II, Formula III,Formula IV, Formula V, or tautomers, stereoisomers, pharmaceuticallyacceptable salts, or hydrates of compounds of Formula I, Formula II,Formula III, Formula IV, and Formula V. The invention also includesmethods of regulating the expression of interlukin-6 (IL-6) and vascularcell adhesion molecule-1 (VCAM-1) in a subject, such as a human,comprising administering a therapeutically effective amount of any ofthe compounds of the invention described herein or a pharmaceuticallyacceptable composition comprising one or more compounds of theinvention.

Definitions

As used in the present specification, the following words, phrases andsymbols are generally intended to have the meanings as set forth below,except to the extent that the context in which they are used indicatesotherwise. The following abbreviations and terms have the indicatedmeanings throughout:

As used herein, “cardiovascular disease” refers to diseases, disordersand conditions of the heart and circulatory system that are mediated byVCAM-1 and/or IL-6. Exemplary cardiovascular diseases, includingcholesterol- or lipid-related disorders, include, but are not limitedto, acute coronary syndrome, angina, arteriosclerosis, atherosclerosis,carotid atherosclerosis, cerebrovascular disease, cerebral infarction,congestive heart failure, congenital heart disease, coronary heartdisease, coronary artery disease, coronary plaque stabilization,dyslipidemias, dyslipoproteinemias, endothelium dysfunctions, familialhypercholeasterolemia, familial combined hyperlipidemia,hypoalphalipoproteinemia, hypertriglyceridemia,hyperbetalipoproteinemia, hypercholesterolemia, hypertension,hyperlipidemia, intermittent claudication, ischemia, ischemiareperfusion injury, ischemic heart diseases, cardiac ischemia, metabolicsyndrome, multi-infarct dementia, myocardial infarction, obesity,peripheral vascular disease, reperfusion injury, restenosis, renalartery atherosclerosis, rheumatic heart disease, stroke, thromboticdisorder, transitory ischemic attacks, and lipoprotein abnormalitiesassociated with Alzheimer's disease, obesity, diabetes mellitus,syndrome X, impotence, multiple sclerosis, Parkinson's diseases and aninflammatory diseases.

As used herein, “inflammatory diseases” includes refers to diseases,disorders and conditions, that are mediated by VCAM-1 and/or IL-6.Exemplary inflammatory diseases, include, but are not limited to,arthritis, asthma, dermatitis, psoriasis, cystic fibrosis, posttransplantation late and chronic solid organ rejection, multiplesclerosis, systemic lupus erythematosus, inflammatory bowel diseases,autoimmune diabetes, diabetic retinopathy, diabetic nephropathy,diabetic vasculopathy, ocular inflammation, uveitis, rhinitis,ischemic-reperfusion injury, post-angioplasty restenosis, chronicobstructive pulmonary disease (COPD), glomerulonephritis, Gravesdisease, gastrointestinal allergies, conjunctivitis, atherosclerosis,coronary artery disease, angina, and small artery disease.

“Subject” refers to an animal, such as a mammal, that has been or willbe the object of treatment, observation, or experiment. The methodsdescribed herein may be useful for both human therapy and veterinaryapplications. In one embodiment, the subject is a human.

As used herein, “treatment” or “treating” refers to an amelioration of adisease or disorder, or at least one discernible symptom thereof. Inanother embodiment, “treatment” or “treating” refers to an ameliorationof at least one measurable physical parameter, not necessarilydiscernible by the patient. In yet another embodiment, “treatment” or“treating” refers to inhibiting the progression of a disease ordisorder, either physically, e.g., stabilization of a discerniblesymptom, physiologically, e.g., stabilization of a physical parameter,or both. In yet another embodiment, “treatment” or “treating” refers todelaying the onset of a disease or disorder. For example, treating acholesterol disorder may comprise decreasing blood cholesterol levels.

As used herein, “prevention” or “preventing” refers to a reduction ofthe risk of acquiring a given disease or disorder.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom.

By “optional” or “optionally” is meant that the subsequently describedevent or circumstance may or may not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which is does not. For example, “optionally substituted aryl”encompasses both “aryl” and “substituted aryl” as defined below. It willbe understood by those skilled in the art, with respect to any groupcontaining one or more substituents, that such groups are not intendedto introduce any substitution or substitution patterns that aresterically impractical, synthetically non-feasible and/or inherentlyunstable.

As used herein, the term “hydrate” refers to a crystal form with eithera stoichiometric or non-stoichiometric amount of water is incorporatedinto the crystal structure.

The term “acyl” term as used herein refers to a carbonyl radicalattached to an alkyl, alkenyl, alkynyl, cycloalkyl, heterocycyl, aryl,or heteroaryl. Exemplary acyl groups include, but are not limited to,acetyl, formyl, propionyl, benzoyl, and the like.

The term “aldehyde” or “formyl” as used herein refers to —CHO.

The term “alkenyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon double bond, suchas a straight or branched group of 2-22, 2-8, or 2-6 carbon atoms,referred to herein as (C₂-C₂₂)alkenyl, (C₂-C₈)alkenyl, and(C₂-C₆)alkenyl, respectively. Exemplary alkenyl groups include, but arenot limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl,pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, and4-(2-methyl-3-butene)-pentenyl.

The term “alkoxy” as used herein refers to an alkyl group attached to anoxygen (—O-alkyl-). “Alkoxy” groups also include an alkenyl groupattached to an oxygen (“alkenyloxy”) or an alkynyl group attached to anoxygen (“alkynyloxy”) groups. Exemplary alkoxy groups include, but arenot limited to, groups with an alkyl, alkenyl or alkynyl group of 1-22,1-8, or 1-6 carbon atoms, referred to herein as (C₁-C₂₂)alkoxy,(C₁-C₈)alkoxy, and (C₁-C₆)alkoxy, respectively. Exemplary alkoxy groupsinclude, but are not limited to methoxy and ethoxy.

The term “alkyl” as used herein refers to a saturated straight orbranched hydrocarbon, such as a straight or branched group of 1-22, 1-8,or 1-6 carbon atoms, referred to herein as (C₁-C₂₂)alkyl, (C₁-C₈)alkyl,and (C₁-C₆)alkyl, respectively. Exemplary alkyl groups include, but arenot limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl,2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl,2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl,hexyl, heptyl, and octyl.

The term “alkynyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon triple bond, suchas a straight or branched group of 2-22, 2-8, or 2-6 carbon atoms,referred to herein as (C₂-C₂₂)alkynyl, (C₂-C₈)alkynyl, and(C₂-C₆)alkynyl, respectively. Exemplary alkynyl groups include, but arenot limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl,methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl, and4-butyl-2-hexynyl.

The term “amide” as used herein refers to the form —NR_(a)C(O)(R_(b))—or —C(O)NR_(b)R_(c), wherein R_(a), R_(b) and R_(c) are eachindependently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl,cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen. The amidecan be attached to another group through the carbon, the nitrogen,R_(b), or R_(c). The amide also may be cyclic, for example R_(b) andR_(c), may be joined to form a 3- to 12-membered ring, such as a 3- to10-membered ring or a 5- or 6-membered ring. The term “amide”encompasses groups such as sulfonamide, urea, ureido, carbamate,carbamic acid, and cyclic versions thereof. The term “amide” alsoencompasses an amide group attached to a carboxy group, e.g.,-amide-COOH or salts such as -amide-COONa, an amino group attached to acarboxy group (e.g., -amino-COOH or salts such as -amino-COONa).

The term “amine” or “amino” as used herein refers to the form—NR_(d)R_(e) or —N(R_(d))R_(e)—, where R_(d) and R_(e) are independentlyselected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, carbamate,cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen. The aminocan be attached to the parent molecular group through the nitrogen. Theamino also may be cyclic, for example any two of R_(d) and R_(e) may bejoined together or with the N to form a 3- to 12-membered ring (e.g.,morpholino or piperidinyl). The term amino also includes thecorresponding quaternary ammonium salt of any amino group. Exemplaryamino groups include alkylamino groups, wherein at least one of R_(d) orR_(e) is an alkyl group.

The term “aryl” as used herein refers to a mono-, bi-, or othermulti-carbocyclic, aromatic ring system. The aryl group can optionallybe fused to one or more rings selected from aryls, cycloalkyls, andheterocyclyls. The aryl groups of this invention can be substituted withgroups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide,amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester,ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl,ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid,sulfonamide, and thioketone. Exemplary aryl groups include, but are notlimited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl,and naphthyl, as well as benzo-fused carbocyclic moieties such as5,6,7,8-tetrahydronaphthyl. Exemplary aryl groups also include, but arenot limited to a monocyclic aromatic ring system, wherein the ringcomprises 6 carbon atoms, referred to herein as “(C₆)aryl.”

The term “arylalkyl” as used herein refers to an alkyl group having atleast one aryl substituent (e.g., -aryl-alkyl-). Exemplary arylalkylgroups include, but are not limited to, arylalkyls having a monocyclicaromatic ring system, wherein the ring comprises 6 carbon atoms,referred to herein as “(C₆)arylalkyl.”

The term “aryloxy” as used herein refers to an aryl group attached to anoxygen atom. Exemplary aryloxy groups include, but are not limited to,aryloxys having a monocyclic aromatic ring system, wherein the ringcomprises 6 carbon atoms, referred to herein as “(C₆)aryloxy.”

The term “arylthio” as used herein refers to an aryl group attached toan sulfur atom. Exemplary arylthio groups include, but are not limitedto, arylthios having a monocyclic aromatic ring system, wherein the ringcomprises 6 carbon atoms, referred to herein as “(C₆)arylthio.”

The term “arylsulfonyl” as used herein refers to an aryl group attachedto a sulfonyl group, e.g., —S(O)₂-aryl-. Exemplary arylsulfonyl groupsinclude, but are not limited to, arylsulfonyls having a monocyclicaromatic ring system, wherein the ring comprises 6 carbon atoms,referred to herein as “(C₆)arylsulfonyl.”

The term “benzyl” as used herein refers to the group —CH₂-phenyl.

The term “bicyclic aryl” as used herein refers to an aryl group fused toanother aromatic or non-aromatic carbocylic or heterocyclic ring.Exemplary bicyclic aryl groups include, but are not limited to, naphthylor partly reduced forms thereof, such as di-, tetra-, orhexahydronaphthyl.

The term “bicyclic heteroaryl” as used herein refers to a heteroarylgroup fused to another aromatic or non-aromatic carbocylic orheterocyclic ring. Exemplary bicyclic heteroaryls include, but are notlimited to 5,6- or 6,6-fused systems, wherein one or both rings containheteroatoms. The term “bicyclic heteroaryl” also encompasses reduced orpartly reduced forms of fused aromatic system wherein one or both ringscontain ring heteroatoms. The ring system may contain up to threeheteroatoms, independently selected from oxygen, nitrogen, and sulfur.The bicyclic system may be optionally substituted with one or moregroups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide,amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester,ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl,ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid,sulfonamide, and thioketone. Exemplary bicyclic heteroaryl's include,but are not limited to, quinazolinyl, benzothiophenyl, benzoxazolyl,benzimidazolyl, benzothiazolyl, benzofuranyl, indolyl, quinolinyl,isoquinolinyl, phthalazinyl, benzotriazolyl, benzopyridinyl, andbenzofuranyl.

The term “carbamate” as used herein refers to the form—R_(g)OC(O)N(R_(h))—, —R_(g)OC(O)N(R_(h))R_(i)—, or —OC(O)NR_(h)R_(i),wherein R_(g), R_(h) and R_(i) are each independently selected fromalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl,heteroaryl, heterocyclyl, and hydrogen. Exemplary carbamates include,but are not limited to, arylcarbamates or heteroaryl carbamates (e.g.,wherein at least one of R_(g), R_(h) and R_(i) are independentlyselected from aryl or heteroaryl, such as pyridine, pyridazine,pyrimidine, and pyrazine).

The term “carbonyl” as used herein refers to —C(O)—.

The term “carboxy” as used herein refers to —COOH or its correspondingcarboxylate salts (e.g., —COONa). The term carboxy also includes“carboxycarbonyl,” e.g. a carboxy group attached to a carbonyl group,e.g., —C(O)—COOH or salts, such as —C(O)—COONa.

The term “cyano” as used herein refers to —CN.

The term “cycloalkoxy” as used herein refers to a cycloalkyl groupattached to an oxygen.

The term “cycloalkyl” as used herein refers to a saturated orunsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group of3-12 carbons, or 3-8 carbons, referred to herein as “(C₃-C₈)cycloalkyl,”derived from a cycloalkane. Exemplary cycloalkyl groups include, but arenot limited to, cyclohexanes, cyclohexenes, cyclopentanes, andcyclopentenes. Cycloalkyl groups may be substituted with alkoxy,aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate,sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.Cycloalkyl groups can be fused to other cycloalkyl saturated orunsaturated, aryl, or heterocyclyl groups.

The term “dicarboxylic acid” as used herein refers to a group containingat least two carboxylic acid groups such as saturated and unsaturatedhydrocarbon dicarboxylic acids and salts thereof. Exemplary dicarboxylicacids include alkyl dicarboxylic acids. Dicarboxylic acids may besubstituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino,aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether,formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen,hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl,sulfonic acid, sulfonamide and thioketone. Dicarboxylic acids include,but are not limited to succinic acid, glutaric acid, adipic acid,suberic acid, sebacic acid, azelaic acid, maleic acid, phthalic acid,aspartic acid, glutamic acid, malonic acid, fumaric acid, (+)/(−)-malicacid, (+)/(−) tartaric acid, isophthalic acid, and terephthalic acid.Dicarboxylic acids further include carboxylic acid derivatives thereof,such as anhydrides, imides, hydrazides (for example, succinic anhydrideand succinimide).

The term “ester” refers to the structure —C(O)O—, —C(O)O—R_(j)—,—R_(k)C(O)O—R_(j)—, or —R_(k)C(O)O—, where O is not bound to hydrogen,and R_(j) and R_(k) can independently be selected from alkoxy, aryloxy,alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, cycloalkyl,ether, haloalkyl, heteroaryl, and heterocyclyl. R_(k) can be a hydrogen,but R_(j) cannot be hydrogen. The ester may be cyclic, for example thecarbon atom and R_(j), the oxygen atom and R_(k), or R_(j) and R_(k) maybe joined to form a 3- to 12-membered ring. Exemplary esters include,but are not limited to, alkyl esters wherein at least one of R_(j) orR_(k) is alkyl, such as —O—C(O)-alkyl, —C(O)—O-alkyl-, and-alkyl-C(O)—O-alkyl-. Exemplary esters also include aryl or heteorarylesters, e.g. wherein at least one of R_(j) or R_(k) is a heteroarylgroup such as pyridine, pyridazine, pyrmidine and pyrazine, such as anicotinate ester. Exemplary esters also include reverse esters havingthe structure —R_(k)C(O)O—, where the oxygen is bound to the parentmolecule. Exemplary reverse esters include succinate, D-argininate,L-argininate, L-lysinate and D-lysinate. Esters also include carboxylicacid anhydrides and acid halides.

The term “ether” refers to the structure —R_(l)O—R_(m-), where R_(l) andR_(m) can independently be alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, and ether. The ether can be attached to the parentmolecular group through R_(l) or R_(m). Exemplary ethers include, butare not limited to, alkoxyalkyl and alkoxyaryl groups. Ethers alsoincludes polyethers, e.g., where one or both of R_(l) and R_(m) areethers.

The terms “halo” or “halogen” or “Hal” as used herein refer to F, Cl,Br, or I.

The term “haloalkyl” as used herein refers to an alkyl group substitutedwith one or more halogen atoms. “Haloalkyls” also encompass alkenyl oralkynyl groups substituted with one or more halogen atoms.

The term “heteroaryl” as used herein refers to a mono-, bi-, ormulti-cyclic, aromatic ring system containing one or more heteroatoms,for example 1-3 heteroatoms, such as nitrogen, oxygen, and sulfur.Heteroaryls can be substituted with one or more substituents includingalkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate,sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.Heteroaryls can also be fused to non-aromatic rings. Illustrativeexamples of heteroaryl groups include, but are not limited to,pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl,pyrazolyl, imidazolyl, (1,2,3)- and (1,2,4)-triazolyl, pyrazinyl,pyrimidilyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl,phenyl, isoxazolyl, and oxazolyl. Exemplary heteroaryl groups include,but are not limited to, a monocyclic aromatic ring, wherein the ringcomprises 2-5 carbon atoms and 1-3 heteroatoms, referred to herein as“(C₂-C₅)heteroaryl.”

The terms “heterocycle,” “heterocyclyl,” or “heterocyclic” as usedherein refer to a saturated or unsaturated 3-, 4-, 5-, 6-, or 7-memberedring containing one, two, or three heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur. Heterocycles can be aromatic(heteroaryls) or non-aromatic. Heterocycles can be substituted with oneor more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl,amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl,ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl,hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl,sulfonic acid, sulfonamide, and thioketone. Heterocycles also includebicyclic, tricyclic, and tetracyclic groups in which any of the aboveheterocyclic rings is fused to one or two rings independently selectedfrom aryl, cycloalkyl, and heterocycle. Exemplary heterocycles includeacridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl,benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl,dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl,imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl,isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl,oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyranyl,pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl, pyridyl,pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl,pyrrolyl, quinolinyl, quinoxaloyl, tetrahydrofuryl,tetrahydroisoquinolyl, tetrahydropyranyl, tetrahydroquinolyl,tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl,thiomorpholinyl, thiopyranyl, and triazolyl.

The terms “hydroxy” and “hydroxyl” as used herein refers to —OH.

The term “hydroxyalkyl” as used herein refers to a hydroxy attached toan alkyl group.

The term “hydroxyaryl” as used herein refers to a hydroxy attached to anaryl group.

The term “ketone” as used herein refers to the structure —C(O)—R_(n)(such as acetyl, —C(O)CH₃ or —R_(n)—C(O)—R_(o)—. The ketone can beattached to another group through R_(n) or R_(o). R_(n) or R_(o) can bealkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or aryl, or R_(n) andR_(o) can be joined to form a 3- to 12-membered ring.

The term “monoester” as used herein refers to an analogue of adicarboxylic acid wherein one of the carboxylic acids is functionalizedas an ester and the other carboxylic acid is a free carboxylic acid orsalt of a carboxylic acid. Examples of monoesters include, but are notlimited to, to monoesters of succinic acid, glutaric acid, adipic acid,suberic acid, sebacic acid, azelaic acid, oxalic, and maleic acid.

The term “nitro” as used herein refers to —NO₂.

The term “perfluoroalkoxy” as used herein refers to an alkoxy group inwhich all of the hydrogen atoms have been replaced by fluorine atoms.

The term “perfluoroalkyl” as used herein refers to an alkyl group inwhich all of the hydrogen atoms have been replaced by fluorine atoms.Exemplary perfluroalkyl groups include, but are not limited to, C₁-C₅perfluoroalkyl, such as trifluoromethyl.

The term “perfluorocycloalkyl” as used herein refers to a cycloalkylgroup in which all of the hydrogen atoms have been replaced by fluorineatoms.

The term “phenyl” as used herein refers to a 6-membered carbocyclicaromatic ring. The phenyl group can also be fused to a cyclohexane orcyclopentane ring_(—) Phenyl can be substituted with one or moresubstituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide,amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester,ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl,ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid,sulfonamide, and thioketone.

The term “phosphate” as used herein refers to the structure —OP(O)O₂—,—R_(x)OP(O)O₂—, —OP(O)O₂R_(y)—, or —R_(x)OP(O)O₂R_(y)—, wherein R_(x)and R_(y) can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocyclyl, and hydrogen.

The term “sulfide” as used herein refers to the structure —R_(z)S—,where R_(z) can be alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl,haloalkyl, heteroaryl, heterocyclyl. The sulfide may be cyclic, forminga 3 to 12-membered ring. The term “alkylsulfide” as used herein refersto an alkyl group attached to a sulfur atom.

The term “sulfinyl” as used herein refers to the structure —S(O)O—,—R_(p)S(O)O—, —R_(p)S(O)OR_(q)—, or —S(O)OR_(q)—, wherein R_(p) andR_(q) can be alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, haloalkyl,heteroaryl, heterocyclyl, and hydroxyl. Exemplary sulfinyl groupsinclude, but are not limited to, alkylsulfinyls wherein at least one ofR_(p) or R_(q) is alkyl, alkenyl, or alkynyl.

The term “sulfonamide” as used herein refers to the structure—(R_(r))—N—S(O)₂—R_(s)— or —R_(t)(R_(r))—N—S(O)₂—R_(s), where R_(t),R_(r), and R_(s) can be, for example, hydrogen, alkyl, alkenyl, alkynyl,aryl, cycloalkyl, and heterocyclyl. Exemplary sulfonamides includealkylsulfonamides (e.g., where R_(s) is alkyl), arylsulfonamides (e.g.,where R_(s) is aryl), cycloalkyl sulfonamides (e.g., where R_(s) iscycloalkyl), and heterocyclyl sulfonamides (e.g., where R_(s) isheterocyclyl).

The term “sulfonate” as used herein refers to —OSO₃—. Sulfonate includessalts such as —OSO₃Na, —OSO₃K and the acid —OSO₃H.

The term “sulfonic acid” refers to —SO₃H— and its corresponding salts(e.g., —SO₃K— and —SO₃Na—).

The term “sulfonyl” as used herein refers to the structure R_(u)SO₂—,where R_(u) can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, andheterocyclyl (e.g., alkylsulfonyl). The term “alkylsulfonyl” as usedherein refers to an alkyl group attached to a sulfonyl group.“Alkylsulfonyl” groups can optionally contain alkenyl or alkynyl groups.

The term “thioketone” refers to the structure —R_(v)—C(S)—R_(w)—. Theketone can be attached to another group through R_(v) or R_(w). R_(v) orR_(w) can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or aryl,or R_(v) and R_(w) can be joined to form a 3- to 12-membered ring.

“Alkyl” groups can be substituted with or interrupted by or branchedwith at least one group selected from alkoxy, aryloxy, alkyl, alkenyl,alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano,cycloalkyl, ester, ether, formyl, halogen, haloalkyl, ketone,heteroaryl, heterocyclyl, hydroxyl, nitro, phosphate, sulfide, sulfinyl,sulfonyl, sulfonic acid, sulfonamide, thioketone, ureido, and N. Thesubstituents may be branched to form a substituted or unsubstitutedheterocycle or cycloalkyl.

“Alkenyl,” “alkynyl”, “alkoxy”, “amino” and “amide” groups can besubstituted with or interrupted by or branched with at least one groupselected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino,aryl, arylalkyl, carbamate, carbonyl, carboxy, cyano, cycloalkyl, ester,ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl,ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid,sulfonamide, thioketone, ureido, and N. The substituents may be branchedto form a substituted or unsubstituted heterocycle or cycloalkyl.

As used herein, a “suitable substituent” refers to a group that does notnullify the synthetic or pharmaceutical utility of the compounds of theinvention or the intermediates useful for preparing them. Examples ofsuitable substituents include, but are not limited to: C₁₋₂₂, C₁₋₈, andC₁₋₆ alkyl, alkenyl or alkynyl; C₁₋₆ aryl, C₂₋₅ heteroaryl; C₃₋₇cycloalkyl; C₁₋₂₂, C₁₋₈, and C₁₋₆ alkoxy; C₆ aryloxy; —CN; —OH; oxo;halo, carboxy; amino, such as —NH(C₁₋₂₂, C₁₋₈, or C₁₋₆ alkyl), —N(C₁₋₂₂,8, and C₁₋₆ alkyl)₂, —NH((C₆)aryl), or —N((C₆)aryl)₂; formyl; ketones,such as —CO(C₁₋₂₂, C₁₋₈, and C₁₋₆ alkyl), —CO((C₆ aryl) esters, such as—CO₂(C₁₋₂₂, C₁₋₈, and C₁₋₆ alkyl) and —CO₂ (C₆ aryl). One of skill inart can readily choose a suitable substituent based on the stability andpharmacological and synthetic activity of the compound of the invention.

As used herein, “inhibiting” refers to blocking, suppressing, or in anyother way, reducing the expression of IL-6 mRNA and/or VCAM-1 mRNA,and/or the level of protein.

As used herein, “reducing” refers to reducing the overall levels of IL-6and/or VCAM-1, e.g., by inhibiting the expression of, eliminating,and/or modifying IL-6 mRNA and/or VCAM-1 mRNA, and/or the level ofprotein.

The term “pharmaceutically acceptable carrier” as used herein refers toany and all solvents, dispersion media, coatings, isotonic andabsorption delaying agents, and the like, that are compatible withpharmaceutical administration. The use of such media and agents forpharmaceutically active substances is well known in the art. Thecompositions may also contain other active compounds providingsupplemental, additional, or enhanced therapeutic functions.

The term “pharmaceutically acceptable composition” as used herein refersto a composition comprising at least one compound as disclosed hereinformulated together with one or more pharmaceutically acceptablecarriers.

The term “pharmaceutically acceptable prodrugs” as used hereinrepresents those prodrugs of the compounds of the present invention thatare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, commensurate with a reasonablebenefit/risk ratio, and effective for their intended use, as well as thezwitterionic forms, where possible, of the compounds of the invention. Adiscussion is provided in Higuchi et al., “Prodrugs as Novel DeliverySystems,” ACS Symposium Series, Vol. 14, and in Roche, E. B., ed.Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporatedherein by reference.

The term “pharmaceutically acceptable salt(s)” refers to salts of acidicor basic groups that may be present in compounds used in the presentcompositions. Compounds included in the present compositions that arebasic in nature are capable of forming a wide variety of salts withvarious inorganic and organic acids. The acids that may be used toprepare pharmaceutically acceptable acid addition salts of such basiccompounds are those that form nontoxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, including but notlimited to sulfate, citrate, matate, acetate, oxalate, chloride,bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate,isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate,tannate, pantothenate, bitartrate, ascorbate, succinate, maleate,gentisinate, fumarate, gluconate, glucaronate, saccharate, formate,benzoate, glutamate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds includedin the present compositions that include an amino moiety may formpharmaceutically acceptable salts with various amino acids, in additionto the acids mentioned above. Compounds included in the presentcompositions, that are acidic in nature are capable of forming basesalts with various pharmacologically acceptable cations. Examples ofsuch salts include alkali metal or alkaline earth metal salts and,particularly, calcium, magnesium, sodium, lithium, zinc, potassium, andiron salts.

The compounds of the disclosure may contain one or more chiral centersand/or double bonds and, therefore, exist as stereoisomers, such asgeometric isomers, enantiomers or diastereomers. The term“stereoisomers” when used herein consist of all geometric isomers,enantiomers or diastereomers. These compounds may be designated by thesymbols “R” or “S,” depending on the configuration of substituentsaround the stereogenic carbon atom. The present invention encompassesvarious stereoisomers of these compounds and mixtures thereof.Stereoisomers include enantiomers and diastereomers. Mixtures ofenantiomers or diastereomers may be designated “(±)” in nomenclature,but the skilled artisan will recognize that a structure may contain animplicit chiral center.

Individual stereoisomers of compounds of the present invention can beprepared synthetically from commercially available starting materialsthat contain asymmetric or stereogenic centers, or by preparation ofracemic mixtures followed by resolution methods well known to those ofordinary skill in the art. These methods of resolution include, but arenot limited to (1) attachment of a mixture of enantiomers to a chiralauxiliary, separation of the resulting mixture of diastereomers byrecrystallization or chromatography and liberation of the optically pureproduct from the auxiliary, (2) salt formation employing an opticallyactive resolving agent, or (3) direct separation of the mixture ofoptical enantiomers on chiral chromatographic columns. Stereoisomericmixtures can also be resolved into their component stereoisomers by wellknown methods, including, but not limited to chiral-phase gaschromatography, chiral-phase high performance liquid chromatography,crystallizing the compound as a chiral salt complex, and/orcrystallizing the compound in a chiral solvent. Stereoisomers can alsobe obtained from stereomerically-pure intermediates, reagents, andcatalysts by well known asymmetric synthetic methods.

Geometric isomers can also exist in the compounds of the presentinvention. The present invention encompasses the various geometricisomers and mixtures thereof resulting from the arrangement ofsubstituents around a carbon-carbon double bond or arrangement ofsubstituents around a carbocyclic ring. Substituents around acarbon-carbon double bond are designated as being in the “Z” or “E”configuration wherein the terms “Z” and “E” are used in accordance withIUPAC standards. Unless otherwise specified, structures depicting doublebonds encompass both the E and Z isomers.

Substituents around a carbon-carbon double bond alternatively can bereferred to as “cis” or “trans,” where “cis” represents substituents onthe same side of the double bond and “trans” represents substituents onopposite sides of the double bond. The arrangements of substituentsaround a carbocyclic ring are designated as “cis” or “trans.” The term“cis” represents substituents on the same side of the plane of the ringand the term “trans” represents substituents on opposite sides of theplane of the ring. Mixtures of compounds wherein the substituents aredisposed on both the same and opposite sides of plane of the ring aredesignated “cis/trans.”

The compounds disclosed herein may exist as tautomers and bothtautomeric forms are intended to be encompassed by the scope of theinvention, even though only one tautomeric structure is depicted. Forexample, any claim to compound A below is understood to includetautomeric structure B, and vice versa, as well as mixtures thereof.

EXEMPLARY EMBODIMENTS

Formula I Methods and Compounds

In certain embodiments, the method for inhibiting the expression of, orreducing IL-6 and/or VCAM-1 in a subject, comprises administering atherapeutically effective amount of at least one compound of Formula I:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, orhydrate thereof, wherein:

R₃ and R₄ are independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₆alkenyl, C₁-C₆ alkynyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, aryloxy, aryl,hydroxyl, amino, amide, oxo, —CN, and sulfonamide; and

R₈ is selected from hydrogen, C₁-C₆ alkyl, C₁-C₆ alkenyl, acyl, andC₁-C₆ alkynyl.

In some embodiments, the method for inhibiting the expression of, orreducing IL-6 and/or VCAM-1 in a subject, comprises administering atherapeutically effective amount of at least one compound of Formula I,wherein:

R₃ and R₄ are independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₆alkenyl, C₁-C₆ alkynyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, aryloxy, aryl,hydroxyl, amino, amide, oxo, —CN, and sulfonamide; and

R₉ and R₁₀ are independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₆alkenyl, C₁-C₆ alkynyl, C₃-C₆ cycloalkyl, aryl, heterocycle, sulfonyl,carbamate, carboxamide, and acyl.

In some embodiments, the method for inhibiting the expression of, orreducing IL-6 and/or VCAM-1 in a subject, comprises administering atherapeutically effective amount of at least one compound of Formula I,wherein:

R₃ and R₄ are independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₆alkenyl, C₁-C₆ alkynyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, aryloxy, aryl,hydroxyl, amino, amido, oxo, —CN, and sulfonamide; and

R₈ is selected from hydrogen, C₁-C₆ alkyl, C₁-C₆ alkenyl, alkynyl, acyl,and C₃-C₆ cycloalkyl.

In some embodiments, the method for inhibiting the expression of, orreducing IL-6 and/or VCAM-1 in a subject, comprises administering atherapeutically effective amount of at least one compound of Formula I,wherein:

U is C═O;

Rc is hydrogen;

Ra₂ is hydrogen;

Ra₁ and Ra₃ are independently selected from C₁-C₆ alkoxy, hydrogen, andhalogen;

Rb₂, Rb₃, Rb₅, and Rb₆ are each hydrogen;

is selected from

R₃ and R₄ are independently selected from hydrogen and C₁-C₆ alkyl;

R₈ is selected from C₁-C₆ alkyl and hydrogen; and

R₉, R₁₀, R₁₁, and R₁₂ are independently selected from C₁-C₆ alkyl,hydrogen, acyl, and sulfonyl.

In some embodiments, the method for inhibiting the expression of, orreducing −6 and/or VCAM-1 in a subject, comprises administering atherapeutically effective amount of at least one compound of Formula I,wherein:

U is C═O;

Rc is hydrogen;

Ra₂ is hydrogen;

Ra₁ and Ra₃ are independently selected from methoxy, hydrogen, andhalogen;

Rb₂, Rb₃, Rb₅, and Rb₆ are each hydrogen;

is selected from

R₃ and R₄ are independently selected from hydrogen and methyl;

R₈ is selected from hydrogen, hydroxyethyl, butyl, acetyl, isopropyl,4-hexanoyl, 4-isobutyryl, benzoyl, 4-fluorobenzoyl, 4-picolinoyl,4-nicotinoyl, 4-isonicotinoyl, thiophene-2-carbonyl,5-chloro-1-methyl-1H-pyrazole-4-carbonyl, 3,3,3-trifluoropropanoyl,2,5-dichlorothiopene-3-carbonyl, cyclopropanecarbonyl, 4-fluorobenzyl,benzyl, 2,2,2-trifluoroethyl, tertbutoxycarbonyl, and formyl;

R₉ and R₁₀ are independently selected from hydrogen, methyl,cyclopropylmethyl, and acetyl; and

R₁₁ and R₁₂ are independently selected from hydrogen, acetyl,methanesulfonyl, dimethylaminocarbonyl, benzoyl, benzyl, ethyl, andisopropyl.

In certain embodiments, the method for inhibiting the expression of, orreducing IL-6 and/or VCAM-1 in a subject, comprises administering atherapeutically effective amount of at least one compound of Formula Iselected from:

-   5,7-dimethoxy-2-(4-morpholinophenyl)quinazolin-4(3H)-one;-   2-(4-((3R,5S)-4-acetyl-3,5-dimethylpiperazin-1-yl)phenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one;-   2-(4-(4-hydroxypiperidin-1-yl)phenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one;-   2-(4-((3R,5S)-4-acetyl-3,5-dimethylpiperazin-1-yl)phenyl)-5-methoxy-7-(2-methoxyethoxy)quinazolin-4(3H)-one;-   2-(4-(4-isopropylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(4-acetylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one;-   N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)acetamide;-   N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)methanesulfonamide;-   3-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)-1,1-dimethylurea;-   2-(4-(4-hexanoylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(4-isobutyrylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(4-benzoylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(4-(4-fluorobenzoyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)benzamide;-   5,7-dimethoxy-2-(4-(4-picolinoylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one;-   5,7-dimethoxy-2-(4-(4-nicotinoylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one;-   2-(4-(4-isonicotinoylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   5,7-dimethoxy-2-(4-(4-(thiophene-2-carbonyl)piperazin-1-yl)phenyl)quinazolin-4(3H)-one;-   2-(4-(4-(5-chloro-1-methyl-1H-pyrazole-4-carbonyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   5,7-dimethoxy-2-(4-(4-(3,3,3-trifluoropropanoyl)piperazin-1-yl)phenyl)quinazolin-4(3H)-one;-   2-(4-(4-(2,5-dichlorothiophene-3-carbonyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(4-(4-fluorobenzyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(4-benzylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)phenyl)quinazolin-4(3H)-one;-   2-(4-(4-butylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(4-acetyl-1,4-diazepan-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(1,4-diazepan-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   5,7-dimethoxy-2-(4-(4-methyl-1,4-diazepan-1-yl)phenyl)quinazolin-4(3H)-one;-   N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)-N-ethylacetamide;-   2-(4-((3R,5S)-4-acetyl-3,5-dimethylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-((3R,5S)-3,5-dimethylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(4-acetyl-3-methylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)pyrrolidin-3-yl)acetamide;-   2-(4-(4-isopropylpiperazin-1-yl)phenyl)-8-methoxyquinazolin-4(3H)-one;-   2-(4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)-N-isopropylacetamide;-   5-chloro-2-(4-(4-isopropylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one;-   2-(4-((3R,5S)-4-isopropyl-3,5-dimethylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   5,7-dimethoxy-2-(4-(piperidin-4-yl)phenyl)quinazolin-4(3H)-one;-   5,7-dimethoxy-2-(4-(3-(methylamino)pyrrolidin-1-yl)phenyl)quinazolin-4(3H)-one;-   tert-butyl    4-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidine-1-carboxylate;-   N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)pyrrolidin-3-yl)-N-methylacetamide;-   2-(4-(4-(isopropylamino)piperidin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(1-acetylpiperidin-4-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   5,7-dimethoxy-2-(4-(3-methylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one;-   N-benzyl-N-(1-(5-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperidin-4-yl)acetamide;-   2-(6-(4-(benzylamino)piperidin-1-yl)pyridin-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one;-   4-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperazine-1-carbaldehyde;-   2-(4-(2-(1-acetylazetidin-3-yl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(3-(cyclopropylmethylamino)pyrrolidin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;    and-   5,7-dimethoxy-2-(4-(4-oxopiperidin-1-yl)phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one,    or a stereoisomer, tautomer, pharmaceutically acceptable salt, or    hydrate thereof.

Another aspect of the invention provides compounds of Formula I:

and stereoisomers, tautomers, pharmaceutically acceptable salts, andhydrates thereof,wherein:

Q and V are independently selected from CH and nitrogen;

U is selected from C═O and SO₂;

W is selected from carbon and nitrogen;

Rc is selected from hydrogen, C₁-C₆ alkyl, and C₃-C₆ cycloalkyl;

Ra₁, Ra₂, and Ra₃ are independently selected from hydrogen, C₁-C₆ alkyl,C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₁-C₆ alkoxy, halogen, amino, amide,hydroxyl, heterocycle, and C₃-C₆ cycloalkyl, wherein Ra₁ and Ra₂ and/orRa₂ and Ra₃ may be connected to form a cycloalkyl or a heterocycle;

Rb₂ and Rb₆ are independently selected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆ alkenyl, C₃-C₆ cycloalkyl, hydroxyl, and amino;

Rb₃ and Rb₅ are independently selected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, hydroxyl, and amino, wherein Rb₂and Rb₃ and/or Rb₅ and Rb₆ may be connected to form a cycloalkyl or aheterocycle;

represents a 3-8 membered ring system wherein:

W is selected from carbon and nitrogen;

Z is selected from CR₅R₇, NR₈, oxygen, sulfur, —S(O)—, and —SO₂—; saidring system being optionally fused to another ring selected fromcycloakyl, heterocycle, and phenyl, and wherein said ring system isselected from, for example, rings having the structures

R₃, R₄, and R₅ are independently selected from hydrogen, C₁-C₆ alkyl,C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, aryl,aryloxy, hydroxyl, amino, amide, oxo, —CN, and sulfonamide;

R₆, and R₇ are independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₆alkenyl, C₁-C₆ alkynyl, C₃-C₆ cycloalkyl, aryl, halogen, hydroxyl, acyl,and —CN;

R₈ is selected from hydrogen, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl,C₃-C₆ cycloalkyl and acyl; and

R₉, R₁₀, R₁₁, and R₁₂ are independently selected from hydrogen, C₁-C₆alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₃-C₆ cycloalkyl, aryl, hydroxyl,sulfonyl, and acyl,

provided that

if Q=CH, then at least one of Ra₁, Ra₂, and Ra₃ is not hydrogen;

if Z═NAc, then only one of Ra₁, Ra₂, and Ra₃ is hydrogen, and Ra₁ is not—OCH₂CH₂OMe;

if Ra₁ and Ra₃ are both OMe, than R₈ is not —C(O)CH₂OH; and

further provided that the compound of Formula I is not5,7-dimethoxy-2-(4-morpholinophenyl)quinazolin-4(3H)-one,5,7-dimethoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one,or2-(4-(1-cyclopentylpiperidin-4-yl)phenyl)-3-methylquinazolin-4(3H)-one.

Some embodiments provide compounds of Formula I, and stereoisomers,tautomers, pharmaceutically acceptable salts, and hydrates thereof,

wherein:

R₃ and R₄ are independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₆alkenyl, C₁-C₆ alkynyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, aryloxy, aryl,hydroxyl, amino, amide, oxo, —CN, and sulfonamide; and

R₈ is selected from hydrogen, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl,acyl, and C₃-C₆ cycloalkyl.

Other embodiments provide compounds of Formula I, and stereoisomers,tautomers, pharmaceutically acceptable salts, and hydrates thereof,

wherein:

R₃ and R₄ are independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₆alkenyl, C₁-C₆ alkynyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, aryloxy, aryl,hydroxyl, amino, amide, oxo, —CN, and sulfonamide; and

R₉ and R₁₀ are independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₆alkenyl, C₁-C₆ alkynyl, C₃-C₆ cycloalkyl, aryl, heterocycle, sulfonyl,carbamate, carboxamide, and acyl.

Still other embodiments provide compounds of Formula I, andstereoisomers, tautomers, pharmaceutically acceptable salts, andhydrates thereof,

wherein:

R₃ and R₄ are independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₆alkenyl, C₁-C₆ alkynyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, aryloxy, aryl,hydroxyl, amino, amide, oxo, —CN, and sulfonamide; and

R₉ and R₁₀ are independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₆alkenyl, C₁-C₆ alkynyl, C₃-C₆ cycloalkyl, aryl, heterocycle, sulfonyl,carboxamide, carbamate, and acyl.

Certain embodiments provide compounds of Formula I, and stereoisomers,tautomers, pharmaceutically acceptable salts, and hydrates thereof,

wherein:

R₃ and R₄ are independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₆alkenyl, C₁-C₆ alkynyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, aryloxy, aryl,hydroxyl, amino, amide, oxo, —CN, and sulfonamide; and

R₈ is selected from hydrogen, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl,acyl, and C₃-C₆ cycloalkyl.

Some embodiments provide compounds of Formula I, and stereoisomers,tautomers, pharmaceutically acceptable salts, and hydrates thereof,

wherein:

U is C═O

Rc is hydrogen;

Ra₂ is hydrogen;

Ra₁ and Ra₃ are independently selected from C₁-C₆ alkoxy, hydrogen, andhalogen;

Rb₂, Rb₃, Rb₅, and Rb₆ are each hydrogen;

is selected from

R₃ and R₄ are independently selected from hydrogen and C₁-C₆ alkyl;

R₈ is selected from C₁-C₆ alkyl, and hydrogen; and

R₉, R₁₀, R₁₁, and R₁₂ are independently selected from C₁-C₆ alkyl,hydrogen, and sulfonyl.

Other embodiments provide compounds of Formula I, and stereoisomers,tautomers, pharmaceutically acceptable salts, and hydrates thereof,

wherein:

U is C═O

Rc is hydrogen;

Ra₂ is hydrogen;

Ra₁ and Ra₃ are independently selected from methoxy, hydrogen, andhalogen;

Rb₂, Rb₃, Rb₅, and Rb₆ are each hydrogen;

is selected from

R₃ and R₄ are independently selected from hydrogen and methyl;

R₃ is selected from hydrogen, hydroxyethyl, butyl, acetyl, isopropyl,4-hexanoyl, 4-isobutyryl, benzoyl, 4-fluorobenzoyl, 4-picolinoyl,4-nicotinoyl, 4-isonicotinoyl, thiophene-2-carbonyl,5-chloro-1-methyl-1H-pyrazole-4-carbonyl, 3,3,3-trifluoropropanoyl,2,5-dichlorothiopene-3-carbonyl, cyclopropanecarbonyl, 4-fluorobenzyl,benzyl, 2,2,2-trifluoroethyl, tertbutoxycarbonyl, and formyl;

R₉ and R₁₀ are independently selected from hydrogen, methyl,cyclopropylmethyl, and acetyl; and

R₁₁ and R₁₂ are independently selected from hydrogen, acetyl,methanesulfonyl, dimethylaminocarbonyl, benzoyl, benzyl, ethyl, andisopropyl.

In one embodiment, compounds of Formula I are selected from:

-   2-(4-((3R,5S)-4-acetyl-3,5-dimethylpiperazin-1-yl)phenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one;-   2-(4-(4-hydroxypiperidin-1-yl)phenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one;-   2-(4-((3R,5S)-4-acetyl-3,5-dimethylpiperazin-1-yl)phenyl)-5-methoxy-7-(2-methoxyethoxy)quinazolin-4(3H)-one;-   2-(4-(4-isopropylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(4-acetylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one;-   N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)acetamide;-   N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)methanesulfonamide-   3-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)-1,1-dimethylurea;-   2-(4-(4-hexanoylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(4-isobutyrylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(4-benzoylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(4-(4-fluorobenzoyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)benzamide;-   5,7-dimethoxy-2-(4-(4-picolinoylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one;-   5,7-dimethoxy-2-(4-(4-nicotinoylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one;-   2-(4-(4-isonicotinoylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   5,7-dimethoxy-2-(4-(4-(thiophene-2-carbonyl)piperazin-1-yl)phenyl)quinazolin-4(3H)-one,-   2-(4-(4-(5-chloro-1-methyl-1H-pyrazole-4-carbonyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   5,7-dimethoxy-2-(4-(4-(3,3,3-trifluoropropanoyl)piperazin-1-yl)phenyl)quinazolin-4(3H)-one;-   2-(4-(4-(2,5-dichlorothiophene-3-carbonyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(4-(4-fluorobenzyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(4-benzylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)phenyl)quinazolin-4(3H)-one;-   2-(4-(4-butylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(4-acetyl-1,4-diazepan-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(1,4-diazepan-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   5,7-dimethoxy-2-(4-(4-methyl-1,4-diazepan-1-yl)phenyl)quinazolin-4(3H)-one;-   N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)-N-ethylacetamide;-   2-(4-((3R,5S)-4-acetyl-3,5-dimethylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(4-((3R,5S)-3,5-dimethylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

-   2-(4-(4-acetyl-3-methylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)pyrrolidin-3-yl)acetamide;-   2-(4-(4-isopropylpiperazin-1-yl)phenyl)-8-methoxyquinazolin-4(3H)-one;-   2-(4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)-N-isopropylacetamide;-   5-chloro-2-(4-(4-isopropylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one;-   2-(4-((3R,5S)-4-isopropyl-3,5-dimethylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   5,7-dimethoxy-2-(4-(piperidin-4-yl)phenyl)quinazolin-4(3H)-one;-   5,7-dimethoxy-2-(4-(3-(methylamino)pyrrolidin-1-yl)phenyl)quinazolin-4(3H)-one;-   tert-butyl    4-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidine-1-carboxylate;-   N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)pyrrolidin-3-yl)-N-methylacetamide;-   2-(4-(4-(isopropylamino)piperidin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(1-acetylpiperidin-4-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   5,7-dimethoxy-2-(4-(3-methylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one;-   N-benzyl-N-(1-(5-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperidin-4-yl)acetamide;-   2-(6-(4-(benzylamino)piperidin-1-yl)pyridin-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one;-   4-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperazine-1-carbaldehyde;-   2-(4-(2-(1-acetylazetidin-3-yl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(3-(cyclopropylmethylamino)pyrrolidin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;    and-   5,7-dimethoxy-2-(4-(4-oxopiperidin-1-yl)phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one,    and tautomers, stereoisomers, pharmaceutically acceptable salts, and    hydrates thereof.

Formula II Methods and Compounds

In certain embodiments, the method for inhibiting the expression of, orreducing IL-6 and/or VCAM-1 in a subject, comprises administering atherapeutically effective amount of at least one compound of Formula II:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, orhydrate thereof, wherein:

Q is CH;

V is N;

U is C═O;

Rc is hydrogen;

Ra₂ is hydrogen;

Ra₁ and Ra₃ are each C₁-C₆ alkyl;

Rb₂, Rb₃, and Rb₆ are each hydrogen;

Rn₁ is hydrogen;

Rn₂ is selected from sulfonyl, heterocycle, and aryl; and

Rb₅ is selected from hydrogen or may be connected with Rn₂ to form aheterocycle.

In some embodiments, the method for inhibiting the expression of, orreducing IL-6 and/or VCAM-1 in a subject, comprises administering atherapeutically effective amount of at least one compound of Formula II,wherein:

Q is CH;

V is N;

U is C═O;

Rc is hydrogen;

Ra₂ is hydrogen;

Ra₁ and Ra₃ are each methoxy;

Rb₂, Rb₃, and Rb₆ are each hydrogen;

Rn₁ is hydrogen;

Rn₂ is selected from methanesulfonyl, pyridin-4-yl, 4-methylphenyl, andpyridin-3-yl; and

Rb₅ is selected from hydrogen or may be connected with Rn₂ to form aheterocycle selected from (2-hydroxymethyl)-1H-pyrrol-5-yl,(2-hydroxyethyl)-1H-pyrrol-5-yl,2-(pyrrolidin-1-yl-ylmethyl)-1H-pyrrol-5-yl,3-(hydroxymethyl)-1H-pyrazol-5-yl,2-(pyrrolidin-1-yl-ylethyl)-1H-pyrrol-5-yl, and2-((dimethylamino)methyl)-1H-pyrrol-5-yl.

In certain embodiments, the method for inhibiting the expression of, orreducing IL-6 and/or VCAM-1 in a subject, comprises administering atherapeutically effective amount of at least one compound of Formula IIselected from:

-   2-(4-(dimethylamino)naphthalen-1-yl)-6,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one;-   2-(2-(hydroxymethyl)-1H-indol-5-yl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(2-(2-hydroxyethyl)-1H-indol-5-yl)-5,7-dimethoxyquinazolin-4(3H)-one;-   5,7-dimethoxy-2-(2-(pyrrolidin-1-ylmethyl)-1H-indol-5-yl)quinazolin-4(3H)-one;-   2-(3-(hydroxymethyl)-1H-indazol-5-yl)-5,7-dimethoxyquinazolin-4(3H)-one;-   5,7-dimethoxy-2-(2-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-5-yl)quinazolin-4(3H)-one;-   2-(2-((dimethylamino)methyl)-1H-indol-5-yl)-5,7-dimethoxyquinazolin-4(3H)-one;-   N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)methanesulfonamide;-   5,7-dimethoxy-2-(4-(pyridin-4-ylamino)phenyl)quinazolin-4(3H)-one;-   5,7-dimethoxy-2-(4-(p-tolylamino)phenyl)quinazolin-4(3H)-one; and-   5,7-dimethoxy-2-(4-(pyridin-3-ylamino)phenyl)quinazolin-4(3H)-one,    or a stereoisomer, tautomer, pharmaceutically acceptable salt, or    hydrate thereof.

Another aspect of the invention provides compounds of Formula II:

and stereoisomers, tautomers, pharmaceutically acceptable salts, andhydrates thereof,wherein:

Q and V are independently selected from CH and nitrogen;

U is selected from C═O and S═O;

R₁ and R₂ are independently selected from hydrogen, and C₁-C₆ alkyl;

Rc is selected from hydrogen, C₁-C₆ alkyl, and C₃-C₆ cycloalkyl;

Ra₁, Ra₂, and Ra₃ are independently selected from hydrogen, C₁-C₆ alkyl,C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, halogen,amino, amide, hydroxyl, and heterocycle, wherein Ra₁ and Ra₂ and/or Ra₂and Ra₃ may be connected to form a cycloalkyl or a heterocycle;

Rb₂ and Rb₆ are independently selected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆ alkenyl, C₃-C₆ cycloalkyl, hydroxyl, and amino;

Rb₃ and Rb₅ are independently selected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, hydroxyl, and amino, wherein

Rb₂ and Rb₃ and/or Rb₅ and/or Rb₆ may be connected to form a cycloalkylor a heterocycle;

Rn₁ is selected from hydrogen, C₁-C₆ alkyl, and C₃-C₆ cycloalkyl; and

Rn₂ is selected from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocycle, aryl,alkenyl, acyl, and sulfonyl, wherein Rn₁ and/or Rn₂ may be connectedwith Rb₃ and/or Rb₅ to form a 5- or 6-membered heterocyclic ring,provided that

at least one of Ra₁, Ra₂, and Ra₃ is not hydrogen; and

Rn₁ and Rn₂ are not both hydrogen, methyl, ethyl, or —CH₂CH₂OH.

Another embodiment provides compounds of Formula II, and stereoisomers,tautomers, pharmaceutically acceptable salts, and hydrates thereof,

wherein:

Q is CH;

V is N;

U is C═O;

Rc is hydrogen;

Ra₂ is hydrogen;

Ra₁ and Ra₃ are each C₁-C₆ alkyl;

Rb₂, Rb₃, and Rb₆ are each hydrogen;

Rn₁ is hydrogen;

Rn₂ is selected from sulfonyl, heterocycle, and aryl; and

Rb₅ is selected from hydrogen or may be connected with Rn₂ to form aheterocycle.

Another embodiment provides compounds of Formula II, and stereoisomers,tautomers, pharmaceutically acceptable salts, and hydrates thereof,

wherein:

Q is CH;

V is N;

U is C═O;

Rc is hydrogen;

Ra₂ is hydrogen;

Ra₁ and Ra₃ are each methoxy;

Rb₂, Rb₃, and Rb₆ are each hydrogen;

Rn₁ is hydrogen;

Rn₂ is selected from methanesulfonyl, pyridin-4-yl, 4-methylphenyl, andpyridin-3-yl; and

Rb₅ is selected from hydrogen or may be connected with Rn₂ to form aheterocycle selected from (2-hydroxymethyl)-1H-pyrrol-5-yl,(2-hydroxyethyl)-1H-pyrrol-5-yl,2-(pyrrolidin-1-yl-ylmethyl)-1H-pyrrol-5-yl,3-(hydroxymethyl)-1H-pyrazol-5-yl,2-(pyrrolidin-1-yl-ylethyl)-1H-pyrrol-5-yl, and2-((dimethylamino)methyl)-1H-pyrrol-5-yl.

In one embodiment, compounds of Formula II are selected from:

-   2-(2-(hydroxymethyl)-1H-indol-5-yl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(2-(2-hydroxyethyl)-1H-indol-5-yl)-5,7-dimethoxyquinazolin-4(3H)-one;-   5,7-dimethoxy-2-(2-(pyrrolidin-1-ylmethyl)-1H-indol-5-yl)quinazolin-4(3H)-one;-   2-(3-(hydroxymethyl)-1H-indazol-5-yl)-5,7-dimethoxyquinazolin-4(3H)-one;-   5,7-dimethoxy-2-(2-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-5-yl)quinazolin-4(3H)-one;-   2-(2-((dimethylamino)methyl)-1H-indol-5-yl)-5,7-dimethoxyquinazolin-4(3H)-one;-   N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)methanesulfonamide;-   5,7-dimethoxy-2-(4-(pyridin-4-ylamino)phenyl)quinazolin-4(3H)-one;-   5,7-dimethoxy-2-(4-(p-tolylamino)phenyl)quinazolin-4(3H)-one; and-   5,7-dimethoxy-2-(4-(pyridin-3-ylamino)phenyl)quinazolin-4(3H)-one,    and tautomers, stereoisomers, pharmaceutically acceptable salts, and    hydrates thereof.

Formula III Methods and Compounds

In certain embodiments, the method for inhibiting the expression of, orreducing IL-6 and/or VCAM-1 in a subject, comprises administering atherapeutically effective amount of at least one compound of FormulaIII:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, orhydrate thereof, wherein:

U is C═O;

Q is selected from CR₁₂ and nitrogen;

V is selected from nitrogen;

Z is selected from unsubstituted C₁-C₆ alkyl;

R₁₂ is selected from C₁-C₆ alkoxy and halogen;

Rc is selected from hydrogen and C₁-C₆ alkyl;

Ra₂ is selected from hydrogen and C₁-C₆ alkoxy;

Ra₁ and Ra₃ are independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₆alkoxy, halogen, and heterocycle;

Rb₂ and Rb₆ are both hydrogen;

Rb₃ and Rb₅ are independently selected from hydrogen and C₁-C₆ alkyl;

X is selected from oxygen and CH₂;

n is selected from 0, 1, 2, 3, or 4; and

G is selected from heterocycle, cycloalkyl, and aryl.

In other embodiments, U is C═O in compounds of Formula III that may beused to inhibit the expression of, or reduce IL-6 and/or VCAM-1 in asubject, wherein:

Q is selected from CR₁₂ and nitrogen;

V is selected from nitrogen;

R₁₂ is selected from methoxy and chlorine;

Rc is selected from hydrogen and (pyrrolidin-1-yl)propyl;

Ra₂ is selected from hydrogen and methoxy;

Ra₁ and Ra₃ are independently selected from hydrogen, methyl, chlorine,fluorine, methoxy, isopropoxy, and pyrrolidin-1-yl;

Rb₂ and Rb₆ are both hydrogen;

Rb₃ and Rb₅ are independently selected from hydrogen and methyl;

is selected from (N,N-dimethylpiperidine-1-carboxamide)-4-oxy,1-acetylpiperidin-4-yloxy, 2-(isoindolin-2-yl)ethoxy,2-(pyrrolidin-1-yl)ethoxy, 3-(pyrrolidin-1-yl)propoxy,4-(pyrrolidin-1-yl)butoxy, (4-acetylpiperazin-1-yl)ethoxy,(1H-imidazol-1-yl)ethoxy, (4-methylpiperazin-1-yl)ethoxy,(piperidin-1-yl)ethoxy, (1-isopropylimidazolidine-2,4-dione)-3-ethoxy,(5-phenylimidazolidine-2,4-dione)-3-ethoxy,(imidazolidine-2,4-dione)-3-methyl, (2-azepan-1-yl)ethoxy,(2-azetidin-1-yl)ethoxy, N-(azetidin-3-yl)acetamide-1-ethoxy,(isoindoline-1,3-dione)-2-ethoxy, (5-oxopyrrolidin-2-yl)methoxy,(4-isopropylpiperazin-1-yl)methyl,N-isopropyl-N-(piperidin-4-methyl)acetamide-1-methyl,(4-(isopropylamino)piperidin-1-yl)methyl, (pyrrolidine-2,5-dione)ethoxy,and (1H-tetrazol-5-yl)methyl.

In certain embodiments, the method for inhibiting the expression of, orreducing IL-6 and/or VCAM-1 in a subject, comprises administering atherapeutically effective amount of at least one compound of Formula IIIselected from:

-   3-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;-   2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   3-(3,5-dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;-   2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)quinazolin-4(3H)-one;-   7-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one;-   5,7-dimethoxy-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)quinazolin-4(3H)-one;-   5,7-dimethoxy-2-(4-(morpholinomethyl)phenyl)quinazolin-4(3H)-one;-   2-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   4-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)-N,N-dimethylpiperidine-1-carboxamide;-   2-(4-(1-acetylpiperidin-4-yloxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(2-(isoindolin-2-yl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-methoxyquinazolin-4(3H)-one;-   5,7-dichloro-2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-4(3H)-one;-   2-(3,5-dimethyl-4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-5,7-dimethoxy-3-(3-(pyrrolidin-1-yl)propyl)quinazolin-4(3H)-one;-   2-(4-(2-(4-acetylpiperazin-1-yl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(2-(1H-imidazol-1-yl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-7-methoxyquinazolin-4(3H)-one;-   2-(3,5-dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(3,5-dimethyl-4-(2-(piperidin-1-yl)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   5,7-dimethoxy-2-(3-methyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-4(3H)-one;-   3-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-1-isopropylimidazolidine-2,4-dione;-   2-(3,5-dimethyl-4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   5,7-dimethoxy-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-4(3H)-one;-   2-(3,5-dimethyl-4-(3-(pyrrolidin-1-yl)propyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(3,5-dimethyl-4-(4-(pyrrolidin-1-yl)butoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(3,    5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-8-methoxyquinazolin-4(3H)-one;-   3-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-5-phenylimidazolidine-2,4-dione;-   3-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)benzyl)imidazolidine-2,4-dione;-   2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-6-methoxyquinazolin-4(3H)-one;-   2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one;-   2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-7-fluoro-5-(pyrrolidin-1-yl)quinazolin-4(3H)-one;-   5-chloro-2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-4(3H)-one;-   2-(4-(2-(azepan-1-yl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-difluoroquinazolin-4(3H)-one;-   2-(4-(2-(azetidin-1-yl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   N-(1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)azetidin-3-yl)acetamide;-   2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-diisopropoxyquinazolin-4(3H)-one;-   8-chloro-2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-4(3H)-one;-   2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-dimethylquinazolin-4(3H)-one;-   2-(2-(4-(6,8-dimethoxy-1-oxo-1,2-dihydroisoquinolin-3-yl)-2,6-dimethylphenoxy)ethyl)isoindoline-1,3-dione;-   2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-diisopropoxypyrido[2,3-d]pyrimidin-4(3H)-one;-   2-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)isoindoline-1,3-dione;-   (S)-2-(3,5-dimethyl-4-((5-oxopyrrolidin-2-yl)methoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-((4-isopropylpiperazin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)benzyl)piperidin-4-yl)-N-isopropylacetamide;-   2-(4-((4-(isopropylamino)piperidin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-((1H-tetrazol-5-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;    and-   1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)pyrrolidine-2,5-dione,    or a stereoisomer, tautomer, pharmaceutically acceptable salt, or    hydrate thereof.

Another aspect of the invention provides compounds of Formula III:

and stereoisomers, tautomers, pharmaceutically acceptable salts, andhydrates thereof,wherein:

Q is selected from CR₁₂ and nitrogen;

is selected from CH and nitrogen;

U is selected from C═O, S═O, and SO₂;

Z is selected from unsubstituted C₁-C₆ alkyl and C₁-C₆ alkyl substitutedwith one or more groups selected from C₁-C₃ alkyl, C₁-C₃ alkoxy,cyclopropyl, hydroxyl, amino, and halogen;

X is selected from oxygen, nitrogen, sulfur, NR₆R₇, and CR₆R₇;

n is selected from 0, 1, 2, 3, 4, or 5;

G is selected from heterocycle, cycloalkyl, and aryl;

R₆, R₇, and R₁₂ are independently selected from hydrogen, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, and halogen;

Rc is selected from hydrogen, C₁-C₆ alkyl, and C₃-C₆ cycloalkyl;

Ra₁, Ra₂, and Ra₃ are independently selected from hydrogen, C₁-C₆ alkyl,C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, halogen,amino, amide, hydroxyl, and heterocycle, wherein Ra₁ and Ra₂ and/or Ra₂and Ra₃ may be connected to form a cycloalkyl or a heterocycle;

Rb₂ and Rb₆ are independently selected from hydrogen, halogen, C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkenyl, hydroxyl, and amino; and

Rb₃ and Rb₅ are independently selected from hydrogen, halogen, C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, hydroxyl, and amino, wherein

Rb₂ and Rb₃ and/or Rb₅ and Rb₆ may be connected to form a cycloalkyl ora heterocycle;

provided that

if X=oxygen and n is 3, then Rc is hydrogen;

at least one of Ra₁, Ra₂, and Ra₃ is not hydrogen;

if Ra₂ or Ra₃ is chloro, then Ra₁ is not hydrogen;

if Ra₁ and Ra₃ are OMe, and Q=CH, then

is not

if Ra₁ and Ra₃ are OMe and Ra₂ is hydrogen, then

is not

and further provided that the compound of Formula III is not2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one,2-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)isoindoline-1,3-dione,3-(3,5-dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6,8-dimethoxyisoquinolin-1(2H)-one,2-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one,5,7-dimethoxy-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)quinazolin-4(3H)-one,or 5,7-dimethoxy-2-(4-(morpholinomethyl)phenyl)quinazolin-4(3H)-one.

Some embodiments provide compounds of Formula III, and stereoisomers,tautomers, pharmaceutically acceptable salts, and hydrates thereof,

wherein:

Q is selected from CR₁₂ and nitrogen;

V is selected from nitrogen;

R₁₂ is selected from C₁-C₆ alkoxy, and halogen;

Rc is selected from hydrogen and C₁-C₆ alkyl;

Ra₂ is selected from hydrogen and C₁-C₆ alkoxy;

Ra₁ and Ra₃ are independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₆alkoxy, halogen, and heterocycle;

Rb₂ and Rb₆ are both hydrogen;

Rb₃ and Rb₅ are independently selected from hydrogen and C₁-C₆ alkyl;

X is selected from oxygen and CH₂;

n is selected from 0, 1, 2, 3, or 4; and

G is selected from heterocycle, cycloalkyl, and aryl.

Some embodiments provide compounds of Formula III, and stereoisomers,tautomers, pharmaceutically acceptable salts, and hydrates thereof,

wherein:

Q is selected from CR₁₂ and nitrogen;

is selected from nitrogen;

R₁₂ is selected from methoxy and chlorine;

Rc is selected from hydrogen and (pyrrolidin-1-yl)propyl;

Ra₂ is selected from hydrogen and methoxy;

Ra₁ and Ra₃ are independently selected from hydrogen, methyl, chlorine,fluorine, methoxy, isopropoxy, and pyrrolidin-1-yl;

Rb₂ and Rb₆ are both hydrogen;

Rb₃ and Rb₅ are independently selected from hydrogen and methyl; and

is selected from (N,N-dimethylpiperidine-1-carboxamide)-4-oxy,1-acetylpiperidin-4-yloxy, 2-(isoindolin-2-yl)ethoxy,2-(pyrrolidin-1-yl)ethoxy, 3-(pyrrolidin-1-yl)propoxy,4-(pyrrolidin-1-yl)butoxy, (4-acetylpiperazin-1-yl)ethoxy,(1H-imidazol-1-yl)ethoxy, (4-methylpiperazin-1-yl)ethoxy,(piperidin-1-yl)ethoxy, (1-isopropylimidazolidine-2,4-dione)-3-ethoxy,(5-phenylimidazolidine-2,4-dione)-3-ethoxy,(imidazolidine-2,4-dione)-3-methyl, (2-azepan-1-yl)ethoxy,(2-azetidin-1-yl)ethoxy, N-(azetidin-3-yl)acetamide-1-ethoxy,(isoindoline-1,3-dione)-2-ethoxy, (5-oxopyrrolidin-2-yl)methoxy,(4-isopropylpiperazin-1-yl)methyl,N-isopropyl-N-(piperidin-4-methyl)acetamide-1-methyl,(4-(isopropylamino)piperidin-1-yl)methyl, (pyrrolidine-2,5-dione)ethoxy,and (1H-tetrazol-5-yl)methyl.

In one embodiment, compounds of Formula III are selected from:

-   4-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)-N,N-dimethylpiperidine-1-carboxamide,-   2-(4-(1-acetylpiperidin-4-yloxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(2-(isoindolin-2-yl)ethoxy)-3,    5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-methoxyquinazolin-4(3H)-one;-   5,7-dichloro-2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-4(3H)-one;-   2-(3,5-dimethyl-4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-5,7-dimethoxy-3-(3-(pyrrolidin-1-yl)propyl)quinazolin-4(3H)-one;-   2-(4-(2-(4-acetylpiperazin-1-yl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-(2-(1H-imidazol-1-yl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-7-methoxyquinazolin-4(3H)-one;-   2-(3,5-dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(3,5-dimethyl-4-(2-(piperidin-1-yl)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   5,7-dimethoxy-2-(3-methyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-4(3H)-one;-   3-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-1-isopropylimidazolidine-2,4-dione;-   2-(3,5-dimethyl-4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   5,7-dimethoxy-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-4(3H)-one;-   2-(3,5-dimethyl-4-(3-(pyrrolidin-1-yl)propyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(3,5-dimethyl-4-(4-(pyrrolidin-1-yl)butoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-8-methoxyquinazolin-4(3H)-one;-   3-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-5-phenylimidazolidine-2,4-dione;-   3-(4-(5,7-di    methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)benzyl)imidazolidine-2,4-dione;-   2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-6-methoxyquinazolin-4(3H)-one;-   2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one;-   2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-7-fluoro-5-(pyrrolidin-1-yl)quinazolin-4(3H)-one;-   5-chloro-2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-4(3H)-one;-   2-(4-(2-(azepan-1-yl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-difluoroquinazolin-4(3H)-one;-   2-(4-(2-(azetidin-1-yl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   N-(1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)azetidin-3-yl)acetamide;-   2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-diisopropoxyquinazolin-4(3H)-one;-   8-chloro-2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-4(3H)-one;-   2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-dimethylquinazolin-4(3H)-one;-   2-(2-(4-(6,8-dimethoxy-1-oxo-1,2-dihydroisoquinolin-3-yl)-2,6-dimethylphenoxy)ethyl)isoindoline-1,3-dione;-   2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-diisopropoxypyrido[2,3-d]pyrimidin-4(3H)-one;-   (S)-2-(3,5-dimethyl-4-((5-oxopyrrolidin-2-yl)methoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(4-((4-isopropylpiperazin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)benzyl)piperidin-4-yl)-N-isopropylacetamide;

2-(4-((4-(isopropylamino)piperidin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(4-((1H-tetrazol-5-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;and

-   1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)pyrrolidine-2,5-dione,    and    tautomers, stereoisomers, pharmaceutically acceptable salts, and    hydrates thereof.

Formula IV Methods and Compounds

In certain embodiments, the method for inhibiting the expression of, orreducing IL-6 and/or VCAM-1 in a subject, comprises administering atherapeutically effective amount of at least one compound of Formula IV:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, orhydrate thereof, wherein:

U is C═O;

is nitrogen;

Rb₂ and Rb₆ are both hydrogen;

Rb₃ and Rb₅ are independently selected from C₁-C₆ alkyl and hydrogen;

02 is selected from C₁-C₆ alkyl and hydrogen; and

Q₁ and Q₃ are independently selected from hydrogen and C₁-C₆ alkoxy.

In some embodiments, U is C═O in compounds of Formula IV that may beused to inhibit the expression of, or reduce IL-6 and/or VCAM-1 in asubject, wherein

V is nitrogen;

Rb₂ and Rb₆ are both hydrogen;

Rb₃ and Rb₅ are independently selected from methyl and hydrogen;

Q₂ is selected from hydrogen, (4-methylpiperazin-1-yl)methyl,morpholinoethyl, morpholinomethyl, and (pyrrolidin-1-yl)ethyl; and

Q₁ and Q₃ are independently selected from hydrogen, benzyloxyethoxy,methoxy, methoxyethoxy, (pyrrolidin-1-yl)ethoxy, phenoxyethoxy, andisopropoxyethoxy.

In one embodiment, the method for inhibiting the expression of, orreducing IL-6 and/or VCAM-1 in a subject, comprises administering atherapeutically effective amount of at least one compound of Formula IVselected from:

-   7-(2-(benzyloxy)ethoxy)-5-methoxy-2-(pyridin-4-yl)quinazolin-4(3H)-one;-   2-(2,6-dimethylpyridin-4-yl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(2,6-dimethylpyridin-4-yl)-5-methoxy-7-(2-methoxyethoxy)quinazolin-4(3H)-one;-   2-(2,6-dimethylpyridin-4-yl)-5,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one;-   2-(2,6-dimethylpyridin-4-yl)-7-methoxy-5-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-4(3H)-one;-   2-(2,6-dimethylpyridin-4-yl)-6-((4-methylpiperazin-1-yl)methyl)quinazolin-4(3H)-one;-   2-(2,6-dimethylpyridin-4-yl)-5-methoxy-7-(2-phenoxyethoxy)quinazolin-4(3H)-one;-   2-(2,6-dimethylpyridin-4-yl)-7-methoxy-5-(2-phenoxyethoxy)quinazolin-4(3H)-one;-   2-(2,6-dimethylpyridin-4-yl)-7-methoxy-5-(2-methoxyethoxy)quinazolin-4(3H)-one;-   2-(2,6-dimethylpyridin-4-yl)-5-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-4(3H)-one;-   2-(2,6-dimethylpyridin-4-yl)-7-(2-isopropoxyethoxy)-5-methoxyquinazolin-4(3H)-one;-   2-(2,6-dimethylpyridin-4-yl)-5,7-bis(2-isopropoxyethoxy)quinazolin-4(3H)-one;-   7-(2-(benzyloxy)ethoxy)-2-(2,6-dimethylpyridin-4-yl)-5-methoxyquinazolin-4(3H)-one;-   2-(2,6-dimethylpyridin-4-yl)-6-(2-morpholinoethyl)quinazolin-4(3H)-one;-   2-(2-methylpyridin-4-yl)-6-(morpholinomethyl)quinazolin-4(3H)-one;-   5-methoxy-7-(2-methoxyethoxy)-2-(2-methylpyridin-4-yl)quinazolin-4(3H)-one;-   2-(2,6-dimethylpyridin-4-yl)-6-(2-(pyrrolidin-1-yl)ethyl)quinazolin-4(3H)-one;-   2-(2,6-dimethylpyridin-4-yl)-5-(2-isopropoxyethoxy)-7-methoxyquinazolin-4(3H)-one;    and-   2-(2,6-dimethylpyridin-4-yl)-7-(2-methoxyethoxy)-5-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-4(3H)-one,    or a stereoisomer, tautomer, pharmaceutically acceptable salt, or    hydrate thereof.

Another aspect of the invention provides compounds of Formula IV:

and stereoisomers, tautomers, pharmaceutically acceptable salts, andhydrates thereof,wherein:

Q₁ is selected from nitrogen and C—Ra₁;

Q₂ is selected from nitrogen and C—Ra₂;

Q₃ is selected from nitrogen and C—Ra₃;

V is selected from CH and nitrogen;

U is selected from C═O and S═O;

Ra₁, Ra₂, and Ra₃ are independently selected from hydrogen, C₁-C₆ alkyl,C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, amino,amide, and heterocycle, wherein Ra₁ and Ra₂ and/or Ra₂ and Ra₃ may beconnected to form a cycloalkyl or a heterocycle;

Rb₂ and Rb₆ are independently selected from hydrogen, halogen, C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkenyl, hydroxyl, and amino; and

Rb₃ and Rb₅ are independently selected from hydrogen, methyl, ethyl,C₃-C₆ cycloalkyl, C₁-C₃ alkoxy, and amino, wherein

Rb₂ and Rb₃ and/or Rb₅ and Rb₆ may be connected to form a cycloalkyl ora heterocycle,

provided that

at least one of Ra₁, Ra₂, and Ra₃ is hydrogen;

if Ra₃ is alkoxy, then Ra₁ is not hydrogen;

if Ra₂ is

then Rb₃ is not hydrogen;

if Rb₂, Rb₅, and Rb₆ are hydrogen, then Rb₃ is not —CH₂OH; and

one of Rb₃ and Rb₅ is not hydrogen.

Other embodiments provide compounds of Formula IV, and stereoisomers,tautomers, pharmaceutically acceptable salts, and hydrates thereof,wherein:

U is C═O;

V is nitrogen;

Rb₂ and Rb₆ are both hydrogen;

Rb₃ and Rb₅ are independently selected from C₁-C₆ alkyl and hydrogen;

Q₂ is selected from C₁-C₆ alkyl and hydrogen; and

Q₁ and Q₃ are independently selected from hydrogen and C₁-C₆ alkoxy.

Another embodiment provides compounds of Formula IV, and stereoisomers,tautomers, pharmaceutically acceptable salts, and hydrates thereof,wherein:

U is C═O;

V is nitrogen;

Rb₂ and Rb₆ are both hydrogen;

Rb₃ and Rb₅ are independently selected from methyl and hydrogen;

Q₂ is selected from hydrogen, (4-methylpiperazin-1-yl)methyl,morpholinoethyl, morpholinomethyl, and (pyrrolidin-1-yl)ethyl; and

Q₁ and Q₃ are independently selected from hydrogen, benzyloxyethoxy,methoxy, methoxyethoxy, (pyrrolidin-1-yl)ethoxy, phenoxyethoxy, andisopropoxyethoxy.

In one embodiment, compounds of Formula IV are selected from:

-   7-(2-(benzyloxy)ethoxy)-5-methoxy-2-(pyridin-4-yl)quinazolin-4(3H)-one;-   2-(2,6-dimethylpyridin-4-yl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(2,6-dimethylpyridin-4-yl)-5-methoxy-7-(2-methoxyethoxy)quinazolin-4(3H)-one;-   2-(2,6-dimethylpyridin-4-yl)-5,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one;-   2-(2,6-dimethylpyridin-4-yl)-7-methoxy-5-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-4(3H)-one;-   2-(2,6-dimethylpyridin-4-yl)-6-((4-methylpiperazin-1-yl)methyl)quinazolin-4(3H)-one;-   2-(2,6-dimethylpyridin-4-yl)-5-methoxy-7-(2-phenoxyethoxy)quinazolin-4(3H)-one;-   2-(2,6-dimethylpyridin-4-yl)-7-methoxy-5-(2-phenoxyethoxy)quinazolin-4(3H)-one;-   2-(2,6-dimethylpyridin-4-yl)-7-methoxy-5-(2-methoxyethoxy)quinazolin-4(3H)-one;-   2-(2,6-dimethylpyridin-4-yl)-5-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-4(3H)-one;-   2-(2,6-dimethylpyridin-4-yl)-7-(2-isopropoxyethoxy)-5-methoxyquinazolin-4(3H)-one;-   2-(2,6-dimethylpyridin-4-yl)-5,7-bis(2-isopropoxyethoxy)quinazolin-4(3H)-one;-   7-(2-(benzyloxy)ethoxy)-2-(2,6-dimethylpyridin-4-yl)-5-methoxyquinazolin-4(3H)-one;-   2-(2,6-dimethylpyridin-4-yl)-6-(2-morpholinoethyl)quinazolin-4(3H)-one;-   2-(2-methylpyridin-4-yl)-6-(morpholinomethyl)quinazolin-4(3H)-one;-   5-methoxy-7-(2-methoxyethoxy)-2-(2-methylpyridin-4-yl)quinazolin-4(3H)-one;-   2-(2,6-dimethylpyridin-4-yl)-6-(2-(pyrrolidin-1-yl)ethyl)quinazolin-4(3H)-one;-   2-(2,6-dimethylpyridin-4-yl)-5-(2-isopropoxyethoxy)-7-methoxyquinazolin-4(3H)-one;    and-   2-(2,6-dimethylpyridin-4-yl)-7-(2-methoxyethoxy)-5-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-4(3H)-one,    and    tautomers, stereoisomers, pharmaceutically acceptable salts, and    hydrates thereof.

Formula V Methods and Compounds

In certain embodiments, the method for inhibiting the expression of, orreducing IL-6 and/or VCAM-1 in a subject, comprises administering atherapeutically effective amount of at least one compound of Formula V:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, orhydrate thereof, wherein:

U is C═O;

Ra₂ is selected from hydrogen and amino;

Ra₁ and Ra₃ are independently selected from hydrogen and C₁-C₆ alkoxy;

Q is CH;

Rb₃ is selected from hydrogen, C₁-C₆ alkyl, and C₁-C₆ alkoxy;

Rb₂ and Rb₆ are both hydrogen;

Y is selected from oxygen;

A is C₁-C₄ alkyl;

D may be absent or present, and if present is selected from hydroxy,heterocycle, and NR₁R₂; and

R₁ and R₂ are independently selected from hydrogen and C₁-C₆ alkyl.

In some embodiments, the method for inhibiting the expression of, orreducing IL-6 and/or VCAM-1 in a subject, comprises administering atherapeutically effective amount of at least one compound of Formula V,wherein:

U is C═O;

Ra₂ is selected from hydrogen and amino;

Ra₁ and Ra₃ are independently selected from hydrogen and C₁-C₆ alkoxy;

Q is CH;

Rb₃ is selected from hydrogen, methyl, and methoxy;

Rb₂ and Rb₆ are both hydrogen;

Y is selected from oxygen;

A is selected from methyl and ethyl;

D may be absent or present, and if present is selected from hydroxy,pyrrolidin-1-yl, and NR₁R₂; and

R₁ and R₂ are independently selected from hydrogen and acetyl.

In one embodiment, the method for inhibiting the expression of, orreducing IL-6 and/or VCAM-1 in a subject, comprises administering atherapeutically effective amount of at least one compound of Formula Vselected from:

-   2-(3,5-dimethoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(3-(2-hydroxyethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(3-(2-hydroxyethoxy)-5-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   5,7-dimethoxy-2-(3-methoxy-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-4(3H)-one;-   N-(2-(3-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-5-methoxyphenoxy)ethyl)acetamide;-   2-(3,5-dimethoxyphenyl)-6-(pyridin-4-ylamino)quinazolin-4(3H)-one;    and-   5,7-dimethoxy-2-(3-methoxyphenyl)quinazolin-4(3H)-one, or a    stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate    thereof.

Another aspect of the invention provides compounds of Formula V:

and stereoisomers, tautomers, pharmaceutically acceptable salts, andhydrates thereof,wherein:

-   Q is selected from CR₆ and nitrogen;-   U is selected from C═O and SO₂;-   Y is selected from oxygen, nitrogen, sulfur, NR₆, CR₆R₇;-   A is C₁-C₄ alkyl, wherein the alkyl chain may be connected to Y, D,    R_(b3) and/or R_(b5) to form a cycloalkyl or heterocycle;-   D may be absent or present, and if present is selected from —OR₁,    —NR₁R₂;-   R₁ and R₂ are independently selected from hydrogen, C₁-C₆ alkyl,    C₃-C₆ cycloalkyl, sulfonamide, carboxamide, acyl, and nitrile,    wherein R₁ and R₂ may be connected to form a cycloalkyl or a    heterocycle;

R₆ and R₇ are independently selected from hydrogen, C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₁-C₆ alkoxy, hydroxyl, and halogen;

Ra₁, Ra₂, and Ra₃ are independently selected from hydrogen, C₁-C₆ alkyl,C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, halogen,amino, amide, hydroxyl, and heterocycle, wherein Ra₁ and Ra₂ and/or Ra₂and Ra₃ may be connected to form a cycloalkyl or a heterocycle;

Rb₂ and Rb₆ are independently selected from hydrogen, halogen, C₁-C₆alkyl, and C₃-C₆ cycloalkyl; and

Rb₃ is selected from hydrogen, halogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl,C₁-C₆ alkoxy, hydroxyl, and amino, wherein

Rb₂ and Rb₃ and/or Rb₅ and Rb₆ may be connected to form a cycloalkyl ora heterocycle,

provided that

at least one of Ra₁, Ra₂, and Ra₃ is not hydrogen;

if Ra₁ and Ra₃ are both hydrogen, and Y=nitrogen, then Ra₂ is nothydrogen, —OAc, or —OMe; and further provided that the compound ofFormula V is not2-(3,5-dimethoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one or2-(3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one.

Some embodiments provide compounds of Formula V and stereoisomers,tautomers, pharmaceutically acceptable salts, and hydrates thereof,wherein:

U is C═O;

Ra₂ is selected from hydrogen and amino;

Ra₁ and Ra₃ are independently selected from hydrogen and C₁-C₆ alkoxy;

Q is CH;

Rb₃ is selected from hydrogen, C₁-C₆ alkyl, and C₁-C₆ alkoxy;

Rb₂ and Rb₆ are both hydrogen;

Y is selected from oxygen;

A is C₁-C₄ alkyl;

D may be absent or present, and if present is selected from hydroxy,heterocycle, and NR, R₂; and

R₁ and R₂ are independently selected from hydrogen and C₁-C₆ alkyl.

Some embodiments provide compounds of Formula V and stereoisomers,tautomers, pharmaceutically acceptable salts, and hydrates thereof,wherein:

U is C═O;

Ra₂ is selected from hydrogen and amino;

Ra₁ and Ra₃ are independently selected from hydrogen and C₁-C₆ alkoxy;

Q is CH;

Rb₃ is selected from hydrogen, methyl, and methoxy;

Rb₂ and Rb₆ are both hydrogen;

Y is selected from oxygen;

A is selected from methyl and ethyl;

D may be absent or present, and if present is selected from hydroxy,pyrrolidin-1-yl, and NR₁R₂; and

R₁ and R₂ are independently selected from hydrogen and acetyl.

In one embodiment, compounds of Formula V are selected from:

-   2-(3-(2-hydroxyethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   2-(3-(2-hydroxyethoxy)-5-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;-   5,7-dimethoxy-2-(3-methoxy-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-4(3H)-one;-   N-(2-(3-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-5-methoxyphenoxy)ethyl)acetamide;-   2-(3,5-dimethoxyphenyl)-6-(pyridin-4-ylamino)quinazolin-4(3H)-one;    and-   5,7-dimethoxy-2-(3-methoxyphenyl)quinazolin-4(3H)-one, and    tautomers, stereoisomers, pharmaceutically acceptable salts, and    hydrates thereof.    Pharmaceutical Compositions

Pharmaceutical compositions of the invention comprise at least onecompound of Formula I, II, III, IV, V, or tautomer, stereoisomer,pharmaceutically acceptable salt or hydrate thereof formulated togetherwith one or more pharmaceutically acceptable carriers. Theseformulations include those suitable for oral, rectal, topical, buccaland parenteral (e.g., subcutaneous, intramuscular, intradermal, orintravenous) administration. The most suitable form of administration inany given case will depend on the degree and severity of the conditionbeing treated and on the nature of the particular compound being used.

Formulations suitable for oral administration may be presented indiscrete units, such as capsules, cachets, lozenges, or tablets, eachcontaining a predetermined amount of a compound of the invention aspowder or granules; as a solution or a suspension in an aqueous ornon-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Asindicated, such formulations may be prepared by any suitable method ofpharmacy which includes the step of bringing into association at leastone compound of the invention as the active compound and a carrier orexcipient (which may constitute one or more accessory ingredients). Thecarrier must be acceptable in the sense of being compatible with theother ingredients of the formulation and must not be deleterious to therecipient. The carrier may be a solid or a liquid, or both, and may beformulated with at least one compound described herein as the activecompound in a unit-dose formulation, for example, a tablet, which maycontain from about 0.05% to about 95% by weight of the at least oneactive compound. Other pharmacologically active substances may also bepresent including other compounds. The formulations of the invention maybe prepared by any of the well known techniques of pharmacy consistingessentially of admixing the components.

For solid compositions, conventional nontoxic solid carriers include,for example, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose,magnesium carbonate, and the like. Liquid pharmacologicallyadministrable compositions can, for example, be prepared by, forexample, dissolving or dispersing, at least one active compound of theinvention as described herein and optional pharmaceutical adjuvants inan excipient, such as, for example, water, saline, aqueous dextrose,glycerol, ethanol, and the like, to thereby form a solution orsuspension. In general, suitable formulations may be prepared byuniformly and intimately admixing the at least one active compound ofthe invention with a liquid or finely divided solid carrier, or both,and then, if necessary, shaping the product. For example, a tablet maybe prepared by compressing or molding a powder or granules of at leastone compound of the invention, which may be optionally combined with oneor more accessory ingredients. Compressed tablets may be prepared bycompressing, in a suitable machine, at least one compound of theinvention in a free-flowing form, such as a powder or granules, whichmay be optionally mixed with a binder, lubricant, inert diluent and/orsurface active/dispersing agent(s). Molded tablets may be made bymolding, in a suitable machine, where the powdered form of at least onecompound of the invention is moistened with an inert liquid diluent.

Formulations suitable for buccal (sub-lingual) administration includelozenges comprising at least one compound of the invention in a flavoredbase, usually sucrose and acacia or tragacanth, and pastilles comprisingthe at least one compound in an inert base such as gelatin and glycerinor sucrose and acacia.

Formulations of the invention suitable for parenteral administrationcomprise sterile aqueous preparations of at least one compound ofFormula I, II, III, IV, V, or tautomers, stereoisomers, pharmaceuticallyacceptable salts, and hydrates thereof, which are approximately isotonicwith the blood of the intended recipient. These preparations areadministered intravenously, although administration may also be effectedby means of subcutaneous, intramuscular, or intradermal injection. Suchpreparations may conveniently be prepared by admixing at least onecompound described herein with water and rendering the resultingsolution sterile and isotonic with the blood. Injectable compositionsaccording to the invention may contain from about 0.1 to about 5% w/w ofthe active compound.

Formulations suitable for rectal administration are presented asunit-dose suppositories. These may be prepared by admixing at least onecompound as described herein with one or more conventional solidcarriers, for example, cocoa butter, and then shaping the resultingmixture.

Formulations suitable for topical application to the skin may take theform of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.Carriers and excipients which may be used include Vaseline, lanoline,polyethylene glycols, alcohols, and combinations of two or more thereof.The active compound (i.e., at least one compound of Formula I, II, III,IV, V, or tautomers, stereoisomers, pharmaceutically acceptable salts,and hydrates thereof) is generally present at a concentration of fromabout 0.1% to about 15% w/w of the composition, for example, from about0.5 to about 2%.

The amount of active compound administered may be dependent on thesubject being treated, the subject's weight, the manner ofadministration and the judgment of the prescribing physician. Forexample, a dosing schedule may involve the daily or semi-dailyadministration of the encapsulated compound at a perceived dosage ofabout 1 μg to about 1000 mg. In another embodiment, intermittentadministration, such as on a monthly or yearly basis, of a dose of theencapsulated compound may be employed. Encapsulation facilitates accessto the site of action and allows the administration of the activeingredients simultaneously, in theory producing a synergistic effect. Inaccordance with standard dosing regimens, physicians will readilydetermine optimum dosages and will be able to readily modifyadministration to achieve such dosages.

A therapeutically effective amount of a compound or compositiondisclosed herein can be measured by the therapeutic effectiveness of thecompound. The dosages, however, may be varied depending upon therequirements of the patient, the severity of the condition beingtreated, and the compound being used. In one embodiment, thetherapeutically effective amount of a disclosed compound is sufficientto establish a maximal plasma concentration. Preliminary doses as, forexample, determined according to animal tests, and the scaling ofdosages for human administration is performed according to art-acceptedpractices.

Toxicity and therapeutic efficacy can be determined by standardpharmaceutical procedures in cell cultures or experimental animals,e.g., for determining the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between toxic and therapeutic effects isthe therapeutic index and it can be expressed as the ratio LD₅₀/ED₅₀.Compositions that exhibit large therapeutic indices are preferable.

Data obtained from the cell culture assays or animal studies can be usedin formulating a range of dosage for use in humans. Therapeuticallyeffective dosages achieved in one animal model may be converted for usein another animal, including humans, using conversion factors known inthe art (see, e.g., Freireich et al., Cancer Chemother. Reports50(4):219-244 (1966) and Table 1 for Equivalent Surface Area DosageFactors).

TABLE 1 Equivalent Surface Area Dosage Factors To: Mouse Rat Monkey DogHuman From: (20 g) (150 g) (3.5 kg) (8 kg) (60 kg) Mouse 1 1/2 1/4 1/6 1/12 Rat 2 1 1/2 1/4 1/7 Monkey 4 2 1 3/5 1/3 Dog 6 4 3/5 1 1/2 Human12 7 3 2 1

The dosage of such compounds lies preferably within a range ofcirculating concentrations that include the ED₅₀ with little or notoxicity. The dosage may vary within this range depending upon thedosage form employed and the route of administration utilized.Generally, a therapeutically effective amount may vary with thesubject's age, condition, and gender, as well as the severity of themedical condition in the subject. The dosage may be determined by aphysician and adjusted, as necessary, to suit observed effects of thetreatment.

In one embodiment, a compound of Formula I, II, III, IV, V or atautomer, stereoisomer, pharmaceutically acceptable salt or hydratethereof, is administered in combination with another therapeutic agent.The other therapeutic agent can provide additive or synergistic valuerelative to the administration of a compound of the invention alone. Thetherapeutic agent can be, for example, a statin; a PPAR agonist, e.g., athiazolidinedione or fibrate; a niacin, a RVX, FXR or LXR agonist; abile-acid reuptake inhibitor; a cholesterol absorption inhibitor; acholesterol synthesis inhibitor; a cholesteryl ester transfer protein(CETP), an ion-exchange resin; an antioxidant; an inhibitor of AcylCoAcholesterol acyltransferase (ACAT inhibitor); a tyrophostine; asulfonylurea-based drug; a biguanide; an alpha-glucosidase inhibitor; anapolipoprotein E regulator; a HMG-CoA reductase inhibitor, a microsomaltriglyceride transfer protein; an LDL-lowing drug; an HDL-raising drug;an HDL enhancer; a regulator of the apolipoprotein A-IV and/orapolipoprotein genes; or any cardiovascular drug.

In another embodiment, a compound of Formula I, II, III, IV, V or atautomer, stereoisomer, pharmaceutically acceptable salt or hydratethereof, is administered in combination with one or moreanti-inflammatory agents. Anti-inflammatory agents can includeimmunosuppressants, TNF inhibitors, corticosteroids, non-steroidalanti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs(DMARDS), and the like. Exemplary anti-inflammatory agents include, forexample, prednisone; methylprenisolone (Medrol®), triamcinolone,methotrexate (Rheumatrex®, Trexall®), hydroxychloroquine (Plaquenil®),sulfasalzine (Azulfidine®), leflunomide (Arava®), etanercept (Enbrel®),infliximab (Remicade®), adalimumab (Humira®), rituximab (Rituxan®),abatacept (Orencia®), interleukin-1, anakinra (Kineret™) ibuprofen,ketoprofen, fenoprofen, naproxen, aspirin, acetominophen, indomethacin,sulindac, meloxicam, piroxicam, tenoxicam, lornoxicam, ketorolac,etodolac, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamicacid, diclofenac, oxaprozin, apazone, nimesulide, nabumetone, tenidap,etanercept, tolmetin, phenylbutazone, oxyphenbutazone, diflunisal,salsalate, olsalazine or sulfasalazine.

Therapeutic Methods

In one embodiment, a method of treating or preventing cardiovascular andinflammatory diseases and related disease states, characterized byaltered expression of markers of inflammation such as IL-6 and/or VCAM-1proliferation, comprises administering to a subject (e.g., a mammal,such as e.g., a human) a therapeutically effective amount of at leastone compound of the invention, i.e., a compound of Formula I, II, III,IV, V, or a tautomer, stereoisomer, pharmaceutically acceptable salt orhydrate thereof. In another embodiment, at least one compound of theinvention may be administered as a pharmaceutically acceptablecomposition, comprising one or more compounds of the invention and apharmaceutically acceptable carrier.

In one embodiment, the inflammatory diseases and related disease statesare those where inhibition of IL-6 and/or VCAM-1 proliferation isdesirable.

In some embodiments, the methods of the invention comprise administeringat least one compound of the invention to a subject, such as a human, asa preventative measure against cardiovascular and inflammatory diseasesand related disease states, such as, for example, atherosclerosis,asthma, arthritis, cancer, multiple sclerosis, psoriasis, andinflammatory bowel diseases, and autoimmune disease(s).

In one embodiment, at least one compound of the invention isadministered as a preventative measure to a subject, such as a human,having a genetic predisposition to cardiovascular and inflammatorydiseases and related disease states, such as, for example, familialhypercholesterolemia, familial combined hyperlipidemia, atherosclerosis,a dyslipidemia, a dyslipoproteinemia, arthritis, cancer, multiplesclerosis, or Alzheimer's disease.

In another embodiment, at least one compound of the present invention isadministered as a preventative measure to a subject, such as a human,having a non-genetic predisposition to a disease including acardiovascular disease or an inflammatory disorder. Examples of suchnon-genetic predispositions include cardiac bypass surgery and PTCA(which can lead to restenosis), an accelerated form of atherosclerosis,diabetes in women, (which can lead to polycystic ovarian disease), andcardiovascular disease (which can lead to impotence). Accordingly,compositions of the invention may be used for the prevention of onedisease or disorder and concurrently treating another (e.g., preventionof polycystic ovarian disease while treating diabetes; prevention ofimpotence while treating a cardiovascular disease).

Angioplasty and open heart surgery, such as coronary bypass surgery, maybe required to treat cardiovascular diseases, such as atherosclerosis.These surgical procedures entail using invasive surgical devices and/orimplants, and are associated with a high risk of restenosis andthrombosis. Accordingly, the compounds of the invention may be used ascoatings on surgical devices (e.g., catheters) and implants (e.g.,stents) to reduce the risk of restenosis and thrombosis associated withinvasive procedures used in the treatment of cardiovascular diseases.

In another embodiment, the compounds of the invention may be used forthe prevention of one disease or disorder while concurrently treatinganother (e.g., prevention of polycystic ovarian disease while treatingdiabetes; prevention of impotence while treating a cardiovasculardisease).

EXAMPLES

The invention is further illustrated by the following non-limitingexamples, wherein the following abbreviations have the followingmeanings. If an abbreviation is not defined, it has its generallyaccepted meaning.

AcOH=acetic acid

BINAP=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl

Boc=N-tert-butoxycarbonyl

TBDMS=tert-butyldimethylsilyl

dba=dibenzylidene acetone

DCM=dichloromethane

DMAP=dimethylaminopyridine

DMF=dimethylformamide

DMSO=dimethylsulfoxide

EDCI=1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide

EtOH=ethanol

EtOAc=ethyl acetate

IBX=1,2-benziodexol-3(1H)-one-1-hydroxy-1-oxide

MeOH=methanol

HOBt=N-hydroxybenzotriazole

THF=tetrahydrofuran

TEA=triethylamine

p-TSA=p-toluenesulfonic acid

TBAF=tetrabutylammonium fluoride

DMA=N,N-dimethylacetamide

DIBAL-H=diisobutylaluminum hydride

TPAP=tetrapropylammonium perruthenate

NMO=N-methylmorpholine N-oxide

DDQ=2,3-dicyano-5,6-dichloro-parabenzoquinone

DME=1,2-dimethoxyethane

TFA=trifluoroacetic acid

DPPF=1,1′-bis(diphenylphosphino)ferrocene

Pd(OAc)₂=palladium(II) acetate

Pd(PPh₃)₄=tetrakis(triphenylphosphine)palladium(0)

Example 1. Preparation of2-(4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one(2)

To a solution of5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (1) (0.68mmol) in DMF (8 mL) was added potassium carbonate (0.68 mmol) and2-bromoethanol (0.68 mmol). The resulting solution was stirred at roomtemperature overnight. Then, the mixture was diluted with water,extracted with EtOAc, washed with brine, dried over anhydrous Na₂SO₄,filtered, and concentrated in vacuo to afford 2. The material waspurified by flash chromatography on silica gel, eluting with 50% to 100%of 92:7:1 CHCl₃/MeOH/concentrated NH₄OH in CH₂Cl₂. The product wasfurther purified by reverse-phase chromatography, eluting with 10% to90% CH₃CN in H₂O, to afford the title compound (0.025 g, 9%). ¹H NMR(300 MHz, DMSO-d₆): δ 11.45 (s, 1H), 8.08 (d, J=8.9 Hz, 2H), 7.00 (d,J=9.1 Hz, 2H), 6.68 (s, 1H), 6.46 (s, 1H), 4.30-4.55 (m, 1H), 3.88 (s,3H), 3.83 (s, 3H), 3.43-3.67 (m, 2H), 3.10-3.43 (m, 7H), 2.77-3.04 (m,1H), 2.31-2.64 (m, 2H). ESI MS m/z 411 [M+H]⁺.

Example 2. Preparation of2-(4-(4-butylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one(7)

To a solution of 1-(N-butyl)-piperazine (3) (7.03 mmol) in DMF (8 mL)was added 4-fluorobenzaldehyde (4) (8.43 mmol) and potassium carbonate(8.43 mmol). The resulting solution was heated to 120° C. for 5 hoursand diluted with water. The solution was extracted with EtOAc, washedwith water, brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated in vacuo. The material was purified by flash chromatographyon silica gel to afford 4-(4-butylpiperazin-1-yl)benzaldehyde (5).

To a solution of 2-amino-4,6-dimethoxybenzamide (6) (1.19 mmol) in DMA(10 mL) was added 4-(4-butylpiperazin-1-yl)benzaldehyde (5) (1.09 mmol),NaHSO₃ (1.30 mmol), and p-TsOH (0.10 mmol). The resulting solution washeated to 155° C. for 4 hours and cooled to room temperature. Thesolution was diluted with water, extracted with EtOAc, washed withbrine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo.The material was purified by flash chromatography on silica gel elutingwith 10% to 50% of 92:7:1 CHCl₃/MeOH/concentrated NH₄OH in CH₂Cl₂, toafford the compound 7 (0.06 g, 13%). ¹H NMR (300 MHz, DMSO-d₆): δ 11.76(s, 1H), 8.09 (d, J=8.9 Hz, 2H), 7.00 (d, J=9.0 Hz, 2H), 6.68 (s, 1H),6.47 (s, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.17-3.42 (m, 4H), 2.39-2.58(m, 4H), 2.23-2.37 (m, 2H), 1.37-1.56 (m, 2H), 1.26-1.37 (m, 2H),0.84-0.94 (m, 3H). APCI MS m/z 423 [M+H]⁺.

Example 3. Preparation of2-(4-(1-acetylpiperidin-4-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one(13)

A solution of 2-(4-bromophenyl)-5,7-dimethoxyquinazolin-4(3H)-one (8)(3.23 mmol), K₂CO₃ (9.69 mmol), PdCl₂(dppf) (0.32 mmol) and tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(9) (3.23 mmol) in DMF (50 mL) was heated to 110° C. overnight. Theresulting solution was concentrated in vacuo and the material waspurified by flash chromatography on silica gel to give tert-butyl4-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate(10).

A solution of tert-butyl4-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate(10) (0.34 mmol) in EtOH (10 mL) and HOAc (5 mL) was purged withnitrogen and 10% Pd/C (0.016 g) was added. The mixture was stirred under1 atmosphere of hydrogen overnight. Then, the solution was filteredthrough Celite, with MeOH washings, and the filtrate was concentrated invacuo. The material was purified by flash chromatography on silica gelto afford tert-butyl4-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidine-1-carboxylate(11).

To a solution of tert-butyl4-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidine-1-carboxylate(11) (0.45 mmol) in 1,4-dioxane (2 mL) was added 4 M HCl in 1,4-dioxane(1 mL). The resulting solution was stirred at room temperature for 5hours. Then, the mixture was concentrated in vacuo and the resultingmaterial was purified by flash chromatography on silica gel to affordcompound 5,7-dimethoxy-2-(4-(piperidin-4-yl)phenyl)quinazolin-4(3H)-one(12).

To a solution of5,7-dimethoxy-2-(4-(piperidin-4-yl)phenyl)quinazolin-4(3H)-one (0.16mmol) in CH₂Cl₂ (10 mL) was added Et₃N (0.32 mmol) and acetyl chloride(0.17 mmol). The resulting solution was stirred at 0° C. overnight. Thesolution was concentrated in vacuo, basified with NaHCO₃, extracted withCH₂Cl₂, and washed with water and brine. The material was dried(Na₂SO₄), filtered, and concentrated to afford the title compound 13(0.020 g, 30%). ¹H NMR (300 MHz, DMSO-d₆): δ 11.93 (s, 1H), 8.11 (d,J=8.3 Hz, 2H), 7.40 (d, J=8.3 Hz, 2H), 6.73 (s, 1H), 6.53 (s, 1H),4.42-4.64 (m, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.06-3.21 (m, 1H),2.77-2.94 (m, 1H), 2.54-2.68 (m, 1H), 2.03 (s, 3H), 1.73-1.91 (m, 2H),1.56-1.73 (m, 1H), 1.36-1.56 (m, 1H), 1.06-1.36 (m, 1H). ESI MS m/z 408[M+H]⁺.

Example 4. Preparation of2-(4-(3-(cyclopropylmethylamino)pyrrolidin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one(15)

A suspension of2-(4-(3-aminopyrrolidin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one(14) (0.21 mmol) in ethanol (30 mL) was treated with PtO₂ (0.050 g)followed by cyclopropanecarbaldehyde (0.100 mL). The reaction wasstirred under 1 atmosphere of hydrogen for 24 hours, filtered throughCelite, with ethanol washes, concentrated, and purified by flashchromatography on silica gel, eluting to afford the title compound 15.

Example 5. Preparation of2-(4-(2-(1-acetylazetidin-3-yl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one(19)

To a solution of N-(1-benzhydryl-azetidin-3-yl)-acetamide (16) (3.57mmol) in ethanol (20 mL) were added palladium hydroxide on carbon (20 wt%, 0.20 g) and concentrated HCl (0.6 mL). The reaction mixture washydrogenated at 50 psi at 40° C. for 2 hours, then filtered and washedwith methanol (50 mL). The filtrate was collected and the solvent wasevaporated, to give N-azetidin-3-yl-acetamide (17).

To a suspension of N-azetidin-3-yl-acetamide (17) (1.99 mmol) and2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (18) (1.00 mmol) inanhydrous DMF (10 mL) was added triethylamine (3 mL). The reactionmixture was stirred at room temperature for 3 days under nitrogen. Thesolvent was evaporated under reduced pressure, water (50 mL) was added,and the precipitated solid was filtered off. The aqueous layer wasextracted with ethyl acetate (2×100 mL). The organic phase was driedover anhydrous Na₂SO₄ and concentrated. The crude compound was purifiedby the Simpliflash system (0-5% 7 N ammonia in methanol and CH₂Cl₂ aseluent) to give the title compound 19 as a white solid.

Example 6. Preparation of2-(2,6-dimethylpyridin-4-yl)-5-(2-isopropoxyethoxy)-7-methoxyquinazolin-4(3H)-one(23)

To a solution of 2-isopropoxy ethanol (21) (57.0 mmol) in anhydrous DMF(10 mL) was added a sodium hydride (60% suspension in mineral oil, 28.54mmol) in small portions at room temperature under nitrogen. After theaddition, the reaction mixture was stirred at room temperature for 30minutes. Then,2-(2,6-dimethyl-pyridin-4-yl)-5,7-difluoro-3H-quinazolin-4-one (20)(2.85 mmol) was added, and the reaction mixture was stirred at roomtemperature for 16 hours. The reaction mixture was cooled to roomtemperature and saturated NH₄Cl solution was added. The product wasextracted with ethyl acetate (3×200 mL). The combined organic layer waswashed with water, brine, dried over anhydrous Na₂SO₄, and evaporated togive crude product (22) as a white solid.

2-(2,6-Dimethyl-pyridin-4-yl)-7-fluoro-5-(2-isopropoxy-ethoxy)-3H-quinazolin-4-one(22) (960 mg, 2.58 mmol) was taken up in anhydrous DMF (10 mL). Sodiummethoxide (25% solution in methanol, 12.9 mmol) was added. After theaddition, the reaction mixture was stirred at 60° C. for 72 hours. Thereaction mixture was cooled to room temperature, and quenched withsaturated solution of NH₄Cl. The product was extracted with ethylacetate (3×200 mL). The combined organic layer was washed with water,brine, dried over Na₂SO₄, and evaporated to give crude product. Thecrude compound was purified by preparative HPLC, to give the titlecompound 23 as a white solid.

Example 7. Preparation of2-(4-((3R,5S)-4-Acetyl-3,5-dimethylpiperazin-1-yl)phenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one

To a solution of 4-fluoro-benzaldehyde (3.0 g, 0.024 mol) and1-(2,6-dimethyl-piperazin-1-yl)-ethanone (3.0 g, 0.019 mol) in anhydrousDMF (15 mL) was added potassium carbonate (6.6 g, 0.048 mol). Thereaction mixture was heated to 130° C. for 32 hours. The DMF was removedand the residue was purified by column chromatography (silica gel230-400 mesh; eluting with 2:1 ethyl acetate and dichloromethane) togive 4-(4-acetyl-3,5-dimethyl-piperazin-1-yl)-benzaldehyde as lightyellow solid (2.31 g, 46.2%).

A mixture of 2-amino-4,6-dimethoxy-nicotinamide (0.25 g, 1.26 mmol),4-(4-acetyl-3,5-dimethyl-piperazin-1-yl)-benzaldehyde (0.43 g, 1.64mmol), p-toluenesulfonic acid monohydrate (0.53 mg, 2.77 mmol) andsodium bisulfite (0.45 g, 2.52 mmol) in N,N-dimethylacetamide (5.0 mL)was stirred at 135° C. under N₂ for 16 hours and then cooled to roomtemperature. The mixture was concentrated to dryness under reducedpressure. Water (40 mL) was added to the residue and stirred for 0.5hours. The precipitate was filtered and the solid was rinsed with waterand dried over Na₂SO₄. The crude solid was purified by columnchromatography (silica gel 230-400 mesh; eluting with 2.5% methanol indichloromethane) to afford the title compound as yellow solid. Yield: 90mg (16.3%). MP 279-279.8° C. ¹H NMR (400 MHz, CDCl₃): δ 10.18 (s, 1H),8.14 (d, J=8.8 Hz, 2H), 6.99 (d, J=8.8 Hz, 2H), 6.20 (s, 1H), 4.78 (bs,1H), 4.12 (s, 3H), 4.02 (s, 3H), 3.70 (d, J=12.0 Hz, 2H) 3.11 (d, J=10Hz, 2H), 2.18 (s, 3H), 1.40 (bs, 6H).

Example 8. Preparation of2-(4-(4-Hydroxypiperidin-1-yl)phenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one

A mixture of 2-amino-4,6-dimethoxy-nicotinamide (0.60 g, 3.0 mmol),4-(4-hydroxy-piperidin-1-yl)-benzaldehyde (0.81 g, 3.9 mmol),p-toluenesulfonic acid monohydrate (1.25 g, 6.6 mmol) and sodiumbisulfite (1.06 g, 6.0 mmol) in N,N-dimethylacetamide (8.0 mL) wasstirred at 135° C. under N₂ for 16 hours and then cooled to roomtemperature. The mixture was concentrated to dryness under reducedpressure. Water (40 mL) was added to the residue and stirred for 0.5hours. The precipitate was filtered and the solid was rinsed with waterand air-dried. The crude solid was purified by column chromatography(silica gel 230-400 mesh; eluting with 4% methanol in dichloromethane)to afford the title compound, as a yellow solid. Yield: 0.29 g (25.2%).MP 284-286° C. ¹H NMR (400 MHz, DMSO-d₆): δ 12.09 (s, 1H), 8.12 (d,J=8.8 Hz, 2H), 7.02 (d, J=8.8 Hz, 2H), 6.32 (s, 1H), 4.73 (d, J=4.4 Hz,1H), 3.94 (s, 3H), 3.89 (s, 3H), 3.72 (m, 3H), 3.05 (m, 2H), 1.80 (m,2H), 1.43 (m, 2H). MS (ES⁺) m/z: 383.06 (M+1).

Example 9. Preparation of2-(4-((3R,5S)-4-Acetyl-3,5-dimethylpiperazin-1-yl)phenyl)-5-methoxy-7-(2-methoxyethoxy)quinazolin-4(3H)-one

To a stirred solution of 2-amino-4,6-difluoro-benzamide (0.66 g, 3.84mmol) and 4-(4-acetyl-3,5-dimethyl-piperazin-1-yl)-benzaldehyde (1.00 g,3.84 mmol) in N,N-dimethyl acetamide (20 mL), was added sodium hydrogensulfite (58.5 wt %, 1.04 g, 5.76 mmol) and p-toluenesulfonic acidmonohydrate (0.88 g, 4.61 mmol) and the reaction mixture was stirred at115° C. for 16 hours. The solvent was evaporated in vacuo, water wasadded, and the precipitated solid was filtered off, to give2-[4-(4-acetyl-3,5-dimethyl-piperazin-1-yl)-phenyl]-5,7-difluoro-3H-quinazolin-4-oneas a yellow solid, which was used in the next step without furtherpurification.

To a solution of2-[4-(4-acetyl-3,5-dimethyl-piperazin-1-yl)-phenyl]-5,7-difluoro-3H-quinazolin-4-one(0.66 g, 1.60 mmol) in DMF (10 mL), a solution of sodium methoxide inmethanol (25 wt %, 3.5 mL, 16.0 mmol) was added and the reaction mixturewas stirred at room temperature for 16 hours. Water was added, acidifiedto pH approximately 4-5 with acetic acid, and the precipitated solid wasfiltered and dried under vacuum to give crude compound, which wasfurther purified by column chromatography (silica gel 230-400 mesh;eluting with 2% methanol solution in dichloromethane) to yield2-[4-(4-acetyl-3,5-dimethyl-piperazin-1-yl)-phenyl]-7-fluoro-5-methoxy-3H-quinazolin-4-oneas a light yellow solid.

To a solution of 2-methoxy-ethanol (1.00 g, 13.4 mmol) in dimethylsulfoxide (4 mL), sodium hydride (60% suspension in mineral oil, 0.50 g,12.5 mmol) was added in portions, and the reaction mixture was stirredat room temperature for 20 minutes. To this reaction mixture was added2-[4-(4-acetyl-3,5-dimethyl-piperazin-1-yl)-phenyl]-7-fluoro-5-methoxy-3H-quinazolin-4-one(0.57 g, 1.34 mmol) and the reaction mixture was stirred at 85° C. for24 hours. Water was added. The mixture was acidified to pH approximately4-5 with acetic acid, and the precipitated solid was filtered to givecrude product, which was purified by column chromatography (silica gel230-400 mesh; eluting with 2% methanol in dichloromethane). Theresulting mixture was purified by preparative HPLC to obtain the titlecompound as a white solid. Yield: 0.140 g (23.2%). MP 225-227° C. ¹H NMR(400 MHz, CDCl₃): δ 8.10 (d, J=8.8 Hz, 2H), 7.08 (d, J=8.8 Hz, 1H), 6.70(d, J=2.4 Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 4.50 (bs, 1H), 4.23 (m, 2H),4.14 (bs, 1H), 3.84 (s, 3H), 3.81 (m, 2H), 3.69 (m, 2H), 3.32 (s, 3H),2.99 (bs, 2H), 2.07 (s, 3H), 1.25 (bs, 6H). MS (ES) m/z: 481.11 (M⁺+1).

Example 10. Preparation of2-(4-(4-Isopropylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

A mixture of 4-fluorobenzaldehyde (0.242 g, 1.95 mmol),1-isopropylpiperazine (0.335 mL, 2.34 mmol), and K₂CO₃ (0.323 g, 2.34mmol) in DMF (2.44 mL) was heated at 120° C. overnight. The mixture wasdiluted with EtOAc (200 mL), washed with 10% aqueous LiCl (3×75 mL) andbrine (75 mL), dried over Na₂SO₄, and filtered. The volatiles wereremoved under vacuum to yield 4-(4-Isopropylpiperazin-1-yl)benzaldehyde(0.504 g) as an orange solid, which was used without furtherpurification.

A mixture of 2-amino-4,6-dimethoxybenzamide (0.100 g, 0.510 mmol),aldehyde from above (0.118 g, 0.510 mmol), NaHSO₃ (94%, 0.0565 g, 0.510mmol), and p-TsOH.H₂O (0.0097 g, 0.051 mmol) in DMA (3.40 mL) was heatedat reflux for 1 hour. The mixture was diluted with EtOAc (250 mL),washed with 10% aqueous LiCl (3×75 mL) and brine (75 mL), dried overNa₂SO₄, filtered and concentrated under vacuum. The resulting residuewas purified over silica gel (12 g, CH₂Cl₂/MeOH) and the product wasfreeze-dried from MeCN/H₂O to provide the title compound (0.0632 g, 30%)as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆): δ 11.74 (s, 1H), 8.09 (d,J=9.05 Hz, 2H), 7.00 (d, J=9.05 Hz, 2H), 6.68 (d, J=2.31 Hz, 1H), 6.47(d, J=2.31 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.31-3.24 (m, 4H),2.74-2.63 (m, 1H), 2.61-2.53 (m, 4H), 1.01 (d, J=6.52 Hz, 6H).

Example 11. Preparation of2-(4-(4-Acetylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

Following the procedure described for Example 10,4-(4-acetylpiperazin-1-yl)benzaldehyde was made from 1-acetylpiperazineand isolated as an orange oil in 67% yield. Following the proceduredescribed for Example 10, the title compound was made from4-(4-acetylpiperazin-1-yl)benzaldehyde and reluxing for 5 hours. Thetitle compound was isolated as a yellow solid in 20% yield. ¹H NMR (300MHz, DMSO-d₆): δ 11.76 (s, 1H), 8.11 (d, J=8.97 Hz, 2H), 7.03 (d, J=8.97Hz, 2H), 6.69 (d, J=2.26 Hz, 1H), 6.47 (d, J=2.26 Hz, 1H), 3.88 (s, 3H),3.84 (s, 3H), 3.62-3.53 (m, 4H), 3.41-3.25 (m, 4H), 2.05 (s, 3H); MS(ESI) m/z 409 [C₂₂H₂₄N₄O₄+H]⁺.

Example 12. Preparation of5,7-Dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one

A mixture of 4-(4-acetylpiperazin-1-yl)benzaldehyde (1.34 g, 5.77 mmol)and 2-amino-4,6-dimethoxybenzamide (1.03 g, 5.24 mmol) in DMA (30 mL)was treated with p-TsOH (0.100 g, 0.524 mmol) and NaHSO₃ (0.578 g, 5.55mmol). The mixture was heated at 155° C. for 6 hours, cooled to roomtemperature, diluted with water (400 mL), and filtered to give brownsolids. The filtrate was extracted with EtOAc (3×100 mL), concentrated,and combined with the brown solids from the filter cake. The combinedsolids were purified by silica gel chromatography, eluting with 92:7:1CHCl₃/MeOH/concentrated NH₄OH to afford2-(4-(4-acetylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-oneas a yellow solid (1.9 g, 90%).

A mixture of2-(4-(4-acetylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one(1.93 g, 4.7 mmol) and 2 M HCl (200 mL) was heated at reflux for 9hours. Then, the mixture was cooled to room temperature, basified to pH8 with 2 N NaOH, extracted with CH₂Cl₂ (3×300 mL), dried over anydrousMgSO₄, filtered, and concentrated. The residue was purified by silicagel chromatography, eluting with 92:7:1 to 6:3:1 CHCl₃/MeOH/concentratedNH₄OH, to afford the title compound (1.13 g, 66%). ¹H NMR (300 MHz,DMSO-d₆): δ 8.08 (d, J=8.9 Hz, 2H), 6.99 (d, J=8.9 Hz, 2H), 6.68 (d,J=2.3 Hz, 1H), 6.47 (d, J=2.3 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H),3.19-3.23 (m, 4H), 2.81-2.84 (m, 4H); APCI MS m/z 367 [M+H]⁺.

Example 13. Preparation ofN-(1-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)acetamide

A solution of ethyl 4-fluorobenzoate (16.5 g, 98.1 mmol) andpiperidin-4-ol (10.0 g, 98.8 mmol) in DMSO (20 mL) was heated at 120° C.under nitrogen for 48 hours. The mixture was cooled to room temperature,poured into water (400 mL), and the solids were filtered off, washedwith water, followed by hexane, to afford ethyl4-(4-hydroxypiperidin-1-yl)benzoate (20.0 g, 82%).

To a solution of ethyl 4-(4-hydroxypiperidin-1-yl)benzoate (8.0 g, 32.1mmol) in CH₂Cl₂ (200 mL) was added Et₃N (23 mL, 165 mmol) undernitrogen, followed by MsCl (5.6 g, 48.9 mmol). The mixture was stirredfor 5 minutes, washed with water (300 mL), dried over anhydrous MgSO₄,filtered, and concentrated to afford ethyl4-(4-(methylsulfonyloxy)piperidin-1-yl)benzoate as a tan solid (10.5 g,100%).

To a solution of ethyl 4-(4-(methylsulfonyloxy)piperidin-1-yl)benzoate(10.5 g, 32.1 mmol) in DMF (50 mL) was added sodium azide (4.17 g, 64.2mmol). The mixture was heated at 80° C. for 5 hours, cooled to roomtemperature, diluted with brine (300 mL), and extracted with ethylacetate (400 mL). The organic phase was washed with brine (2×300 mL),dried over anyhydrous MgSO₄, filtered, and concentrated, to afford ethyl4-(4-azidopiperidin-1-yl)benzoate as a yellow solid (7.62 g, 87%).

To a solution of ethyl 4-(4-azidopiperidin-1-yl)benzoate (7.62 g, 27.8mmol) in dioxane (190 mL) was added acetic acid (27 mL) and water (54mL). Then, 10% Pd/C (0.750 g) was added and the mixture was hydrogenatedunder 1 atmosphere of hydrogen for 5 hours. The mixture was filteredthrough Celite, concentrated, and 0.5 M HCl (500 mL) was added. Thesolution was washed with ethyl acetate (2×300 mL) and the aqueous phasebasified with ammonium hydroxide, to pH 12. The aqueous phase wassaturated with sodium chloride, extracted with CH₂Cl₂ (2×300 mL), driedover anhydrous MgSO₄, filtered, and concentrated, to afford ethyl4-(4-aminopiperidin-1-yl)benzoate.

To a solution of ethyl 4-(4-aminopiperidin-1-yl)benzoate (1.65 g, 6.65mmol) in CH₂Cl₂ (200 mL) was added Et₃N (1.35 g, 13.3 mmol), followed byacetyl chloride (0.573 g, 7.3 mmol). The reaction mixture was stirred atroom temperature for 5 minutes, washed with brine (300 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated, to afford ethyl4-(4-acetamidopiperidin-1-yl)benzoate as a white solid (1.9 g, 100%).

A solution of ethyl 4-(4-acetamidopiperidin-1-yl)benzoate (0.123 g, 0.42mmol) in CH₂Cl₂ (10 mL) under nitrogen at −78° C. was treated withDIBAL-H (1.0M in hexanes, 0.950 mL, 0.95 mmol) dropwise, via a syringe.After 20 minutes, the mixture was warmed to room temperature, stirredfor 1 hour, and quenched with 10% Rochelle's salt. After stirring for 10minutes, CH₂Cl₂ (50 mL) was added, and the stirring was continued for 15additional minutes. The layers were separated and the aqueous phase wasextracted with CH₂Cl₂ (50 mL) and ethyl acetate (50 mL). The combinedorganic phases were dried (MgSO₄), filtered, concentrated, and purifiedby flash chromatography on silica gel, eluting with 100% ethyl acetateto 10% MeOH/ethyl acetate to affordN-(1-(4-(hydroxymethyl)phenyl)piperidin-4-yl)acetamide as a white solid(0.025 g, 24%).

A mixture of N-(1-(4-(hydroxymethyl)phenyl)piperidin-4-yl)acetamide(0.380 g, 1.53 mmol), TPAP (0.026 g, 0.08 mmol), NMO (0.268 g, 2.30mmol), and molecular sieves (3 Angstrom, 0.300 g) in CH₂Cl₂ was stirredat room temperature for 19 hours. The mixture was filtered throughCelite, concentrated, and purified by flash chromatography on silicagel, eluting with 100% ethyl acetate to 10% MeOH/ethyl acetate, toafford N-(1-(4-formylphenyl)piperidin-4-yl)acetamide as a white solid(0.280 g, 74%).

A mixture of N-(1-(4-formylphenyl)piperidin-4-yl)acetamide (0.280 g,1.14 mmol), 2-amino-4,6-dimethoxybenzamide (0.224 g, 1.14 mmol), p-TsOH(0.022 g, 0.114 mmol), and NaHSO₃ (0.125 g, 1.21 mmol) in DMA was heatedat 155° C. for 6 hours. The reaction mixture was cooled, diluted withwater (100 mL), basified with saturated NaHCO₃, and extracted with ethylacetate (3×150 mL). The organic phase was concentrated and purified byflash chromatography on silica gel, eluting with 1:1 CH₂Cl₂/(92:7:1CHCl₃/MeOH/concentrated NH₄OH) to 100% 92:7:1 CHCl₃/MeOH/concentratedNH₄OH. Further purification by reverse-phase HPLC, eluting with 10% to90% CH₃CN in H₂O with 0.1% TFA, afforded the title compound as a yellowsolid (0.140 g, 29%): ¹H NMR (300 MHz, DMSO-d₆): δ 11.74 (s, 1H), 8.08(d, J=9.0 Hz, 2H), 7.83 (d, J=7.7 Hz, 1H), 7.01 (d, J=9.0 Hz, 2H), 6.68(d, J=2.3 Hz, 1H), 6.46 (d, J=2.3 Hz, 1H), 3.7-3.89 (m, 9H), 2.92-3.00(m, 2H), 1.76-1.85 (m, 5H), 1.36-1.48 (m, 2H); APCI MS m/z 423 [M+H]⁺.

Example 14. Preparation ofN-(1-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)methanesulfonamide

A mixture of2-(4-(4-aminopiperidin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one(0.105 g, 0.28 mmol), methanesulfonylchloride (0.035 g, 0.30 mmol), andEt₃N (0.057 g. 0.56 mmol) in CH₂Cl₂ (10 mL) was stirred at roomtemperature under nitrogen for 2 hours. The mixture was concentrated,redissolved in THF (5 mL), 2 M NaOH (5 mL) added and stirred for 20minutes. The pH was adjusted to 8 with 1 M HCl and the mixture extractedwith CH₂Cl₂ (3×150 mL). The organic phase was dried over anhydrousMgSO₄, filtered, and concentrated. The residue was purified by silicagel chromatography, eluting with 1:1 CH₂Cl₂/(92:7:1CHCl₃/MeOH/concentrated NH₄OH) to 100% 92:7:1 CHCl₃/MeOH/concentratedNH₄OH. Further purification by reverse-phase HPLC. eluting with 10% to90% CH₃CN in H₂O with 0.1% TFA. afforded the title compound as a yellowsolid (0.075 g, 58%). ¹H NMR (300 MHz, DMSO-d₆): δ11.75 (s, 1H), 8.08(d, J=9.0 Hz, 2H), 7.13 (d, J=7.3 Hz, 1H), 7.00 (d, J=9.0 Hz, 2H), 6.66(d, J=2.3 Hz, 1H), 6.46 (d, J=2.3 Hz, 1H), 3.81-3.94 (m, 8H), 3.34-3.47(m, 1H), 2.90 (m, 6H), 1.87-1.95 (m, 2H), 1.42-1.54 (m, 2H); ESI MS m/z459 [M+H]⁺.

Example 15. Preparation of3-(1-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)-1,1-dimethylurea

A mixture ofN-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)acetamide(0.250 g, 0.59 mmol) and 2 M HCl (20 mL) was heated at reflux for 24hours. The mixture was basified with 2 M NaOH to pH 8, extracted withCH₂Cl₂ (3×150 mL), dried over anhydrous MgSO4, filtered, andconcentrated to afford2-(4-(4-aminopiperidin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one asa yellow solid (0.215 g, 96%).

A mixture of2-(4-(4-aminopiperidin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one(0.105 g, 0.28 mmol), dimethylcarbamic chloride (0.032 g, 0.30 mmol),and Et₃N (0.085 g, 0.84 mmol) in THF (10 mL) was stirred at roomtemperature for 18 hours. The mixture was then heated at reflux for 24hours, then cooled to room temperature. 2 M NaOH (20 mL) was added andthe mixture was stirred for 30 minutes. The reaction mixture wasadjusted to pH 8, extracted with CH₂Cl₂ (3×100 mL), dried over anhydrousMgSO₄, filtered, and concentrated. The residue was dissolved inCHCl₃/MeOH and concentrated, then CH₃CN was added and concentrated toafford the title compound as a white solid (0.065 g, 51%): ¹H NMR (300MHz, CDCl₃): δ 11.72 (s, 1H), 8.08 (d, J=9.0 Hz, 2H), 7.00 (d, J=9.0 Hz,2H), 6.78 (d, J=2.2 Hz, 1H), 6.46 (d, J=2.2 Hz, 1H), 5.99 (d, J=7.8 Hz,1H), 3.90-3.94 (m, 2H), 3.88 (s, 3H), 3.83 (s, 3H), 3.66-3.69 (m, 1H),2.88-2.93 (m, 2H), 2.76 (s, 6H), 1.75-1.80 (m, 2H), 1.45-1.52 (m, 2H);ESI MS m/z 452 [M+H]⁺.

Example 16. Preparation of2-(4-(4-Hexanoylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

To a solution of5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.120 g,0.32 mmol) in CH₂Cl₂ (10 mL) was added Et₃N (0.06 mL, 0.48 mmol) andhexanoyl chloride (0.03 mL, 0.28 mmol). The resulting solution wasstirred at room temperature for 1 hour. The mixture was concentrated invacuo. The material was purified by flash chromatography, eluting with2% to 10% of MeOH/CH₂Cl₂, to afford the title compound (0.050 g, 38%).¹H NMR (300 MHz, DMSO-d₆): δ 11.79 (s, 1H), 8.11 (d, J=8.7 Hz, 2H), 7.03(d, J=8.8 Hz, 2H), 6.68 (s, 1H), 6.47 (s, 1H), 3.75-4.05 (m, 6H),3.47-3.73 (m, 4H), 3.17-3.43 (m, 4H), 2.20-2.40 (m, 2H), 1.41-1.62 (m,2H), 1.15-1.38 (m, 4H), 0.76-0.98 (m, 3H); APCI MS m/z 465 [M+H]⁺.

Example 17. Preparation of2-(4-(4-Isobutyrylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

To a solution of5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.150 g,0.40 mmol) in CH₂Cl₂ (10 mL) was added Et₃N (0.08 mL, 0.60 mmol) andisobutyryl chloride (0.03 mL, 0.36 mmol). The resulting solution wasstirred at room temperature for 1 hour. The solution was concentrated invacuo and the residue was purified by flash chromatography on silicagel, eluting with 2% to 10% of MeOH/CH₂Cl₂. The solid was furtherpurified by flash chromatography on silica gel, eluting with 0% to 5% ofMeOH/EtOAc, to afford the title compound (0.080 g, 50%): ¹H NMR (300MHz, DMSO-d₆): δ 11.78 (s, 1H), 8.11 (d, J=9.0 Hz, 2H), 7.03 (d, J=9.1Hz, 2H), 6.68 (s, 1H), 6.47 (s, 1H), 3.76-3.92 (m, 6H), 3.52-3.71 (m,4H), 3.16-3.44 (m, 4H), 2.83-3.00 (m, 1H), 1.02 (d, J=6.8 Hz, 6H); APCIMS m/z 437 [M+H]⁺.

Example 18. Preparation of2-(4-(4-Benzoylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

To a solution of5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.150 g,0.40 mmol) in CH₂Cl₂ (10 mL) was added Et₃N (0.08 mL, 0.60 mmol) andbenzoyl chloride (0.04 mL, 0.36 mmol). The resulting solution wasstirred at room temperature for 3 hours. The solution was concentratedin vacuo. The material was purified by flash chromatography on silicagel eluting with 0% to 10% of MeOH/EtOAc to afford the title compound(0.110 g, 64%). ¹H NMR (300 MHz, DMSO-d₆): δ 11.79 (s, 1H), 8.11 (d,J=8.7 Hz, 2H), 7.37-7.54 (m, 5H), 7.04 (d, J=8.9 Hz, 2H), 6.68 (s, 1H),6.47 (s, 1H), 3.61-4.03 (m, 8H), 3.23-3.62 (m, 6H); ESI MS m/z 471[M+H]⁺.

Example 19. Preparation of2-(4-(4-(4-Fluorobenzoyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

To a solution of5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.150 g,0.40 mmol) in CH₂Cl₂ (10 mL) was added Et₃N (0.08 mL, 0.60 mmol) and4-fluorobenzoyl chloride (0.04 mL, 0.36 mmol). The resulting solutionwas stirred at room temperature for 3 hours. The solution wasconcentrated in vacuo and the residue was purified by flashchromatography on silica gel, eluting with 0% to 10% of MeOH/EtOAc, toafford the title compound (0.080 g, 45%). ¹H NMR (300 MHz, DMSO-d₆): δ11.79 (s, 1H), 8.11 (d, J=8.8 Hz, 2H), 7.44-7.62 (m, 2H), 7.21-7.39 (m,2H), 7.04 (d, J=9.0 Hz, 2H), 6.68 (s, 1H), 6.47 (s, 1H), 3.64-3.94 (m,8H), 3.22-3.60 (m, 6H); APCI MS m/z 489 [M+H]⁺.

Example 20. Preparation ofN-(1-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)benzamide

To a solution of ethyl 4-(4-aminopiperidin-1-yl)benzoate (3.0 g, 12.1mmol) in CH₂Cl₂ under nitrogen was added Et₃N (2.45 g, 24.2 mmol),followed by benzoyl chloride (1.70 g, 12.1 mmol). The mixture wasstirred at room temperature overnight, washed with brine (200 mL), driedover anhydrous MgSO₄, filtered, and concentrated. The resulting solidswere triturated with hexanes to afford ethyl4-(4-benzamidopiperidin-1-yl)benzoate as a yellow solid (4.2 g, 100%).

A solution of ethyl 4-(4-benzamidopiperidin-1-yl)benzoate (4.2 g, 11.9mmol) in THF (400 mL) was cooled to 0° C. under nitrogen and treatedwith DIBAL-H (1.0 M in THF, 47 mL, 47 mmol). The mixture was warmed toroom temperature and stirred for 1 hour. Then, the reaction mixture wasquenched with Rochelle's salt (10% aqueous), concentrated to remove theTHF, brine (300 mL) was added, and the organic phase was extracted withCH₂Cl₂ (3×200 mL), dried over anhydrous MgSO₄, filtered, andconcentrated, to affordN-(1-(4-(hydroxymethyl)phenyl)piperidin-4-yl)benzamide as a yellow solidthat was used without further purification.

To a solution of N-(1-(4-(hydroxymethyl)phenyl)piperidin-4-yl)benzamide(1.1 g, 3.5 mmol) in CH₂Cl₂ (250 mL) was added TPAP (0.123 g, 0.35 mmol)and NMO (0.623 g, 5.3 mmol). After 1 hour, the mixture was filteredthrough Celite, concentrated, and purified by silica gel chromatography,eluting with 30% ethyl acetate/hexanes to 100% ethyl acetate, to affordN-(1-(4-formylphenyl)piperidin-4-yl)benzamide as a white solid (0.350 g,32%).

A mixture of N-(1-(4-formylphenyl)piperidin-4-yl)benzamide (0.350 g,1.10 mmol), NaHSO₃ (0.180 g, 1.70 mmol) and p-TsOH (0.022 g, 0.11 mmol)and 2-amino-4,6-dimethoxybenzamide (0.223 g, 1.10 mmol) in DMA (10 mL)was heated at 150° C. overnight. The mixture was concentrated in vacuo,and the residue was dissolved in EtOAc and washed with H₂O and brine,dried (Na₂SO₄), filtered and concentrated in vacuo. The resulting solidwas purified by silica gel chromatography eluting with 10% to 50%CHCl₃/MeOH/concentrated NH₄OH in CH₂Cl₂ to afford the title compound(0.050 g, 10%): ¹H NMR (300 MHz, DMSO-d₆): δ 11.75 (s, 1H), 8.26 (d,J=7.4 Hz, 1H), 8.10 (d, J=9.0 Hz, 2H), 7.83 (d, J=6.9 Hz, 2H), 7.44-7.49(m, 3H), 7.05 (d, J=8.8 Hz, 2H), 6.68 (s, 1H), 6.46 (s, 1H), 3.93-4.17(m, 3H), 3.88 (s, 3H), 3.83 (s, 3H), 2.91-3.08 (m, 2H), 1.82-1.93 (m,2H), 1.52-1.72 (m, 2H); APCI MS m/z 485 [M+H]⁺.

Example 21. Preparation of5,7-Dimethoxy-2-(4-(4-picolinoylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one

To a solution of picolinic acid (0.066 g, 0.54 mmol) in THF (20 mL) wasadded HOBt (0.079 g, 0.59 mmol), EDCI (0.113 g, 0.59 mmol), Et₃N (0.08mL, 0.59 mmol) and5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.200 g,0.54 mmol). The resulting solution was stirred overnight at roomtemperature. The solution was concentrated in vacuo and the resultingsolid was purified by flash chromatography on silica gel, eluting with50% to 100% of 92:7:1 CHCl₃/MeOH/concentrated NH₄OH in CH₂Cl₂, to affordthe title compound (0.160 g, 62%): ¹H NMR (300 MHz, DMSO-d₆): δ 11.69(s, 1H), 8.53-8.70 (m, 1H), 8.11 (d, J=8.9 Hz, 2H), 7.86-8.04 (m, 1H),7.64 (d, J=7.8 Hz, 1H), 7.44-7.57 (m, 1H), 7.04 (d, J=9.1 Hz, 2H), 6.69(s, 1H), 6.47 (s, 1H), 3.74-3.97 (m, 8H), 3.53-3.68 (m, 2H), 3.41-3.53(m, 2H), 3.23-3.39 (m, 2H). APCI MS m/z 472 [M+H]⁺.

Example 22. Preparation of5,7-Dimethoxy-2-(4-(4-nicotinoylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one

To a solution of nicotinic acid (0.066 g, 0.54 mmol) in THF (20 mL) wasadded HOBt (0.079 g, 0.59 mmol), EDCI (0.113 g, 0.59 mmol), Et₃N (0.08mL, 0.59 mmol) and5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.200 g,0.54 mmol). The resulting solution was stirred overnight at roomtemperature. The solution was concentrated in vacuo and the resultingsolid was purified by flash chromatography on silica gel, eluting with10% to 60% of 92:7:1 CHCl₃/MeOH/concentrated NH₄OH in CH₂Cl₂, to affordthe title compound (0.050 g, 19%): ¹H NMR (300 MHz, DMSO-d₆): δ 11.79(s, 1H), 8.59-8.78 (m, 2H), 8.12 (d, J=8.8 Hz, 2H), 7.82-7.99 (m, 1H),7.37-7.60 (m, 1H), 7.04 (d, J=9.1 Hz, 2H), 6.69 (s, 1H), 6.47 (s, 1H),3.63-3.97 (m, 8H), 3.20-3.63 (m, 6H). APCI MS m/z 472 [M+H]⁺.

Example 23. Preparation of2-(4-(4-Isonicotinoylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

To a solution of isonicotinic acid (0.083 g, 0.68 mmol) in THF (20 mL)was added HOBt (0.099 g, 0.74 mmol), EDCI (0.141 g, 0.74 mmol), Et₃N(0.10 mL, 0.74 mmol) and5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.250 g,0.68 mmol). The resulting solution was stirred overnight at roomtemperature. The solution was concentrated in vacuo and the resultingmaterial was purified by flash chromatography on silica gel, elutingwith 10% to 60% of 92:7:1 CHCl₃/MeOH/concentrated NH₄OH in CH₂Cl₂, toafford the title compound (0.110 g, 34%). ¹H NMR (300 MHz, DMSO-d₆): δ11.79 (s, 1H), 8.58-8.79 (m, 2H), 8.12 (d, J=9.0 Hz, 2H), 7.45 (d, J=6.0Hz, 2H), 7.04 (d, J=9.0 Hz, 2H), 6.69 (s, 1H), 6.47 (s, 1H), 3.64-4.06(m, 9H), 3.22-3.54 (m, 5H). APCI MS m/z 472 [M+H]⁺.

Example 24. Preparation of5,7-Dimethoxy-2-(4-(4-(thiophene-2-carbonyl)piperazin-1-yl)phenyl)quinazolin-4(3H)-one

To a solution of 2-thiophenecarboxylic acid (0.087 g, 0.68 mmol) in THF(20 mL) was added HOBt (0.099 g, 0.74 mmol), EDCI (0.141 g, 0.74 mmol),Et₃N (0.10 mL, 0.74 mmol) and5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.250 g,0.68 mmol). The resulting solution was stirred at room temperature for 4hours. The solution was concentrated in vacuo. The material was purifiedby flash chromatography, eluting with 0% to 50% of 92:7:1CHCl₃/MeOH/concentrated NH₄OH in CH₂Cl₂, to afford the title compound(0.100 g, 30%). ¹H NMR (300 MHz, DMSO-d₆): δ 11.78 (s, 1H), 8.12 (d,J=9.0 Hz, 2H), 7.75-7.84 (m, 1H), 7.46-7.53 (m, 1H), 7.12-7.20 (m, 1H),7.03 (d, J=9.1 Hz, 2H), 6.69 (d, J=2.3 Hz, 1H), 6.47 (d, J=2.3 Hz, 1H),3.88 (s, 3H), 3.83 (s, 3H), 3.74-3.92 (m, 4H), 3.37-3.49 (m, 4H). APCIMS m/z 477 [M+H]⁺.

Example 25. Preparation of2-(4-(4-(5-Chloro-1-methyl-1H-pyrazole-4-carbonyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

To a mixture of5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.150 g,0.41 mmol) and 5-chloro-1-methyl-1H-pyrazole-4-carbonyl chloride (0.073g, 0.41 mmol) in CH₂Cl₂ (50 mL), was added Et₃N (0.086 mL, 0.62 mmol)and the reaction stirred under nitrogen at room temperature for 1 hour.The residue was concentrated and purified by flash chromatography onsilica gel, eluting with 70% CH₂Cl₂/(92:7:1 CHCl₃/MeOH/concentratedNH₄OH) to 100% (92:7:1 CHCl₃/MeOH/concentrated NH₄OH), to afford thetitle compound as a white solid (0.159 g, 76%). ¹H NMR (500 MHz,DMSO-d₆): δ 11.78 (s, 1H), 8.12 (d, J=9.0 Hz, 2H), 7.77 (s, 1H), 7.04(d, J=9.1 Hz, 2H), 6.69 (d, J=2.3 Hz, 1H), 6.47 (d, J=2.3 Hz, 1H), 3.88(s, 3H), 3.80-3.87 (m, 6H), 3.63-3.80 (m, 4H), 3.38-3.44 (m, 4H). APCIMS m/z 509 [M+H]⁺.

Example 26. Preparation of5,7-Dimethoxy-2-(4-(4-(3,3,3-trifluoropropanoyl)piperazin-1-yl)phenyl)quinazolin-4(3H)-one

To a solution of5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.200 g,0.54 mmol) in THF (10 mL) was added EDCI (0.105 g, 0.54 mmol), HOBt(0.074 g, 0.54 mmol), Et₃N (0.08 mL, 0.54 mmol) and trifluoropropionicacid (0.070 g, 0.54 mmol). The reaction was stirred at room temperaturefor 4 hours and concentrated in vacuo. Purification by flashchromatography, eluting with 20% to 100% of 92:7:1CHCl₃/MeOH/concentrate NH₄OH in CH₂Cl₂, afforded the title compound(0.135 g, 52%). ¹H NMR (300 MHz, DMSO-d₆): δ 11.78 (s, 1H), 8.10 (d,J=9.0 Hz, 2H), 7.03 (d, J=9.0 Hz, 2H), 6.68 (d, J=2.3 Hz, 1H), 6.47 (d,J=2.3 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.70-3.78 (m, 2H), 3.60-3.67(m, 4H), 3.34-3.38 (m, 4H). APCI MS m/z 477 [M+H]⁺.

Example 27. Preparation of2-(4-(4-(2,5-Dichlorothiophene-3-carbonyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

To a mixture of5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.150 g,0.41 mmol) and 2,5-dichlorothiophene-3-carbonyl chloride (0.088 g, 0.41mmol) in CH₂Cl₂ was added Et₃N (0.086 mL, 0.62 mmol) and the mixturestirred at room temperature under nitrogen for 30 minutes. The mixturewas concentrated and purified by silica gel chromatography, eluting with70% CH₂Cl₂/(92:7:1 CHCl₃/MeOH/concentrated NH₄OH) to 100% (92:7:1CHCl₃/MeOH/concentrated NH₄OH), to afford the title compound as a lightyellow solid (0.177 g, 79%). ¹H NMR (300 MHz, DMSO-d₆): δ 11.80 (s, 1H),8.12 (d, J=9.0 Hz, 2H), 7.27 (s, 1H), 7.05 (d, J=9.0 Hz, 2H), 6.69 (d,J=2.3 Hz, 1H), 6.48 (d, J=2.3 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H),3.73-3.82 (m, 2H), 3.38-3.44 (m, 6H). APCI MS m/z 545 [M+H]⁺.

Example 28. Preparation of2-(4-(4-(Cyclopropanecarbonyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

To a solution of5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.150 g,0.40 mmol) in CH₂Cl₂ (10 mL) was added Et₃N (0.08 mL, 0.60 mmol), andcarbonyl chloride (0.03 mL, 0.36 mmol). The resulting solution wasstirred overnight at room temperature. The solution was concentrated invacuo and the material was purified by flash chromatography on silicagel eluting with 0% to 50% of 92:7:1 CHCl₃/MeOH/concentrated NH₄OH inCH₂Cl₂ to afford the title compound (0.100 g, 63%). ¹H NMR (300 MHz,DMSO-d₆): δ 11.78 (s, 1H), 8.12 (d, J=8.9 Hz, 2H), 7.04 (d, J=9.2 Hz,2H), 6.63-6.74 (m, 1H), 6.39-6.52 (m, 1H), 3.73-3.95 (m, 8H), 3.51-3.73(m, 2H), 3.21-3.49 (m, 4H), 1.93-2.10 (m, 1H), 0.56-0.83 (m, 4H). APCIMS m/z 435 [M+H]⁺.

Example 29. Preparation of2-(4-(4-(4-Fluorobenzyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

To a solution of5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.200 g,0.55 mmol) in DMF (5 mL) was added 4-fluorobenzyl bromide (0.07 mL, 0.55mmol) and K₂CO₃ (0.15 g, 1.10 mmol). The reaction was stirred at roomtemperature for 2 hours then diluted with H₂O and the solids filteredoff to afford the title compound (0.17 g, 65%) as a light brown solid.¹H NMR (300 MHz, DMSO-d₆): δ 11.76 (br s, 1H), 8.09 (d, J=8.1 Hz, 2H),7.26-7.52 (m, 2H), 7.08-7.25 (m, 2H), 7.00 (d, J=8.0 Hz, 2H), 6.68 (s,1H), 6.46 (s, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.51 (s, 2H), 3.08-3.41(m, 4H), 2.23-2.68 (m, 4H). APCI MS m/z 475 [M+H]⁺.

Example 30. Preparation of2-(4-(4-Benzylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

Following the method described for Example 29 above, the title compoundwas made from benzyl bromide in 45% yield. ¹H NMR (300 MHz, DMSO-d₆): δ11.76 (s, 1H), 8.09 (d, J=8.6 Hz, 2H), 7.26-7.43 (m, 5H), 7.00 (d, J=8.8Hz, 2H), 6.68 (s, 1H), 6.46 (s, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.53(s, 2H), 3.23-3.40 (m, 4H), 2.38-2.63 (m, 4H). APCI MS m/z 457 [M+H]⁺.

Example 31. Preparation of2-(4-(4-(2,2,2-Trifluoroethyl)piperazin-1-yl)phenyl)quinazolin-4(3H)-one

To a mixture of 2-aminobenzamide (1.0 g, 7.35 mmol) and4-(4-acetylpiperazin-1-yl)benzaldehyde (1.71 g, 7.35 mmol) in DMA (60mL) was added p-TsOH (0.140 g, 0.73 mmol) and NaHSO₃ (0.841 g, 8.1mmol). The reaction mixture was heated at 150° C. for 21 hours,concentrated to half-volume, diluted with water (300 mL), extracted withCH₂Cl₂ (2×200 mL), washed with brine (200 mL), dried over anhydrousMgSO₄, filtered, and concentrated. The residue was purified by silicagel chromatography, eluting with 100% CH₂Cl₂ to 100% (92:7:1CHCl₃/MeOH/concentrated NH₄OH), to afford2-(4-(4-acetylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one as a yellowsolid (2.27 g, 89%).

A mixture of 2-(4-(4-acetylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one(2.27 g, 6.5 mmol) and 2 N HCl (100 mL) were heated at 100° C. for 4hours. Then, the mixture was cooled to room temperature, basified to pH8 with 2 N NaOH, extracted with CH₂Cl₂ (3×150 mL), dried over anhydrousMgSO₄, filtered, and concentrated to afford2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one as a pale yellow solid(1.8 g, 90%).

To a mixture of 2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.325g, 1.06 mmol) in THF (50 mL) was added Hünig's base (0.192 g, 1.48mmol), followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.295g, 1.3 mmol). The reaction mixture was heated at reflux for 15 hours,concentrated, and purified by flash chromatography on silica gel,eluting with 100% CH₂Cl₂ to 100% ethyl acetate, to afford the titlecompound as an off-white solid (0.385 g, 94%). ¹H NMR (300 MHz,DMSO-d₆): δ 12.27 (br s, 1H), 8.10-8.14 (m, 3H), 7.76-7.82 (m, 1H), 7.67(d, J=7.8 Hz, 1H), 7.42-7.47 (m, 1H), 7.05 (d, J=9.1 Hz, 2H), 3.21-3.34(m, 6H), 2.73-2.78 (m, 4H). APCI MS m/z 389 [M+H]⁺.

Example 32. Preparation of2-(4-(4-Acetyl-1,4-diazepan-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

A mixture of 4-fluorobenzaldehyde (1.56 g, 12.6 mmol),1-(1,4-diazepan-1-yl)ethanone (1.5 g, 10.5 mmol), and K₂CO₃ (1.74 g,12.6 mmol) in DMF (10 mL) were heated at 120° C. for 20 hours. Themixture was cooled to room temperature and diluted with water. Themixture was extracted with ethyl acetate and the organic phase washedwith brine, dried over anhydrous MgSO₄, filtered, and concentrated. Theresidue was purified by flash chromatography on silica gel, eluting with50% ethyl acetate/hexanes to 100% ethyl acetate to 10% methanol/ethylacetate, to afford 4-(4-acetyl-1,4-diazepan-1-yl)benzaldehyde (1.8 g,70%).

To a mixture of 2-amino-4,6-dimethoxybenzamide (0.377 g, 1.92 mmol) and4-(4-acetyl-1,4-diazepan-1-yl)benzaldehyde (0.520 g, 2.11 mmol) in DMA(20 mL) was added NaHSO₃ (0.240 g, 2.3 mmol) followed by p-TsOH (0.037g, 0.192 mmol) and the reaction heated at 150° C. for 6 hours. Themixture was cooled to room temperature, diluted with CH₂Cl₂ (150 mL),washed with brine (2×150 mL), dried over anhydrous MgSO₄, filtered, andconcentrated. The residue was purified by flash chromatography on silicagel, eluting with 1:1 CH₂Cl₂/92:7:1 CHCl₃/MeOH/concentrated NH₄OH to100% 92:7:1 CHCl₃/MeOH/concentrated NH₄OH, to afford the title compound(0.333 g, 41%) as a yellow solid. ¹H NMR (300 MHz, CDCl₃): δ 9.12 (s,1H), 7.88-7.91 (m, 2H), 6.78-6.82 (m, 3H), 6.42 (d, J=2.2 Hz, 1H), 3.98(s, 3H), 3.93 (s, 3H), 3.62-3.80 (m, 6H), 3.36-3.48 (m, 2H), 1.98-2.12(m, 5H). ESI MS m/z 421 [M−H]⁻.

Example 33. Preparation of2-(4-(1,4-Diazepan-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

A mixture of2-(4-(4-acetyl-1,4-diazepan-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one(0.135 g, 0.32 mmol) and 2 N HCl (10 mL) was heated at 100° C. for 4hours. Then, the reaction mixture was cooled to room temperature,basified to pH 8, and extracted with CH₂Cl₂ (8×125 mL). The residue waspurified by flash chromatography on silica gel, eluting with 1:1CH₂Cl₂/92:7:1 CHCl₃/MeOH/concentrated NH₄OH to 100% 92:7:1CHCl₃/MeOH/concentrated NH₄OH, to afford the title compound (0.040 g,33%) as a yellow solid. ¹H NMR (300 MHz, CDCl₃): δ 8.98 (s, 1H), 7.86(d, J=9.0 Hz, 2H), 6.76-6.79 (m, 3H), 6.40 (d, J=2.3 Hz, 1H), 3.98 (s,3H), 3.92 (s, 3H), 3.61-3.69 (m, 5H), 3.05 (t, J=4.9 Hz, 2H), 2.83 (t,J=5.7 Hz, 2H), 1.92 (t, J=5.4 Hz, 2H). ESI MS m/z 379 [M−H]⁻.

Example 34. Preparation of5,7-Dimethoxy-2-(4-(4-methyl-1,4-diazepan-1-yl)phenyl)quinazolin-4(3H)-one

To a solution of2-(4-(1,4-diazepan-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.150g, 0.39 mmol) in DMF (20 mL) was added CH₃I (0.067 g, 0.47 mmol) andHünig's Base (0.138 mL, 0.79 mmol). The reaction mixture was heated at50° C. for 1.5 hours, cooled to room temperature, diluted with ethylacetate (150 mL), washed with brine (2×100 mL), dried over anhydrousMgSO₄, filtered, and concentrated. The residue was purified by flashchromatography on silica gel, eluting with 1:1 CH₂Cl₂/92:7:1CHCl₃/MeOH/concentrated NH₄OH to 100% 92:7:1 CHCl₃/MeOH/concentratedNH₄OH, to afford the title compound (0.035 g, 23%) as a white solid. ¹HNMR (300 MHz, DMSO-d₆): δ 11.66 (s, 1H), 8.06 (d, J=9.0 Hz, 2H), 6.78(d, J=9.0 Hz, 2H), 6.65 (d, J=2.2 Hz, 1H), 6.44 (d, J=2.2 Hz, 1H), 3.87(s, 3H), 3.83 (s, 3H), 3.57-3.59 (m, 2H), 3.52 (t, J=6.1 Hz, 2H),2.60-2.64 (m, 2H), 2.45-2.50 (m, 2H), 2.26 (s, 3H), 1.89-1.99 (m, 2H).ESI MS m/z 395 [M+H]⁺.

Example 35. Preparation ofN-(1-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)-N-ethylacetamide

To a solution of 4-acetamidopiperidine (2.5 g, 17.5 mmol) in DMF (10 mL)was added 4-fluorobenzaldehyde (2.2 g, 17.5 mmol) and K₂CO₃ (2.9 g, 21.2mmol). The reaction was heated at 120° C. for 4 hours, diluted with H₂O,and extracted with EtOAc. The organics were washed sequentially with H₂Oand brine, dried (Na₂SO₄), filtered, and concentrated in vacuo, toafford N-(1-(4-formylphenyl)piperidin-4-yl)acetamide (3.1 g, 92%).

A 60% suspension in oil of NaH (0.113 g, 2.8 mmol) was added to a 0° C.solution of N-(1-(4-formylphenyl)piperidin-4-yl)acetamide (0.700 g, 2.8mmol) in DMF (10 mL) and stirred for 35 minutes. To this mixture wasadded Etl (0.23 mL, 2.8 mmol) and the reaction was warmed to roomtemperature for 2 hours, quenched with H₂O, and extracted with EtOAc.The organics were washed with brine, dried over anhydrous Na₂SO₄,filtered, and concentrated in vacuo. Purification by flashchromatography on silica gel, eluting with 0% to 5% MeOH/CH₂Cl₂,afforded N-ethyl-N-(1-(4-formylphenyl)piperidin-4-yl)acetamide (0.490 g,64%).

A mixture of N-ethyl-N-(1-(4-formylphenyl)piperidin-4-yl)acetamide(0.385 g, 1.40 mmol), NaHSO₃ (0.162 g, 1.50 mmol), and p-TsOH (0.024 g,0.12 mmol) were added to a solution of 2-amino-4,6-dimethoxybenzamide(0.250 g, 1.20 mmol) in DMA (10 mL). The reaction was stirred at 150° C.for 4 hours and then cooled to room temperature overnight. The mixturewas diluted with H₂O and extracted with EtOAc. The organics were washedwith brine, dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo. Purification by flash chromatography on silica gel, eluting with2% to 10% MeOH/CH₂Cl₂, afforded the title compound (0.300 g, 55%) as ayellow solid. ¹H NMR (300 MHz, DMSO-d₆): mixture of rotamers δ 11.76 (s,1H), 8.08 (d, J=8.7 Hz, 2H), 7.02 (d, J=8.7 Hz, 2H), 6.67 (d, J=2.0 Hz,1H), 6.46 (d, J=2.0 Hz, 1H), 4.29-4.33 (m, 0.5H), 3.99-4.03 (m, 2H),3.88 (s, 3H), 3.83 (s, 3H), 3.12-3.25 (m, 2H), 2.81-2.93 (m, 2H), 2.07(s, 1.5H), 2.01 (s, 1.5H), 1.59-1.74 (m, 4.5H), 1.10 (t, J=6.7 Hz,1.5H), 0.99 (t, J=6.7 Hz, 1.5H). ESI MS m/z 451 [M+H]⁺.

Example 36. Preparation of2-(4-((3R,5S)-4-Acetyl-3,5-dimethylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

A mixture of 4-fluorobenzaldehyde (2.0 g, 16.1 mmol),2,6-dimethylpiperazine (2.2 g, 19.3 mmol), and K₂CO₃ (2.7 g, 19.3 mmol)in DMF (10 mL) was heated at 120° C. for 4 hours. Then, the reaction wasdiluted with H₂O and extracted with EtOAc. The organics were washed withbrine, dried (Na₂SO₄), filtered and concentrated in vacuo. Purificationby flash chromatography on silica gel eluting with 3% to 10% MeOH/CH₂Cl₂afforded 4-(3,5-dimethylpiperazin-1-yl)benzaldehyde (2.0 g, 57%).

A solution of 4-(3,5-dimethylpiperazin-1-yl)benzaldehyde (1.0 g, 4.6mmoL) in CH₂Cl₂ (15 mL) was cooled to 0° C. and treated with Et₃N (0.64mL, 4.6 mmol) followed by acetyl chloride (0.33 mL, 4.6 mmol). Thereaction stirred for 30 minutes, then concentrated in vacuo.Purification by flash chromatography on silica gel, eluting with 0% to50% EtOAc/CH₂Cl₂, afforded4-(4-acetyl-3,5-dimethylpiperazin-1-yl)benzaldehyde (1.0 g, 83%).

A mixture of 4-(4-acetyl-3,5-dimethylpiperazin-1-yl)benzaldehyde (0.580g, 2.20 mmol), NaHSO₃ (0.260 g, 2.40 mmol), and p-TsOH (0.039 g, 0.20mmol) was added to a solution of 2-amino-4,6-dimethoxybenzamide (0.400g, 2.20 mmol) in DMA (15 mL). The reaction was stirred at 120° C. for 4hours and then cooled to room temperature overnight. The mixture wasdiluted with H₂O and extracted with EtOAc. The organics were washed withbrine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo.Purification by flash chromatography on silica gel, eluting with 2% to10% MeOH/CH₂Cl₂, afforded the title compound (0.400 g, 46%) as a yellowsolid. ¹H NMR (300 MHz, DMSO-d₆): δ 11.78 (br s, 1H), 8.10 (d, J=8.9 Hz,2H), 7.05 (d, J=9.0 Hz, 2H), 6.68 (d, J=2.3 Hz, 1H), 6.46 (d, J=2.3 Hz,1H), 4.01-4.64 (m, 2H), 3.71-3.95 (m, 8H), 2.87-3.07 (m, 2H), 2.06 (s,3H), 1.25 (d, J=6.2 Hz, 6H). ESI MS m/z 437 [M+H]⁺.

Example 37. Preparation of2-(4-((3R,5S)-3,5-Dimethylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

A solution of2-(4-(4-acetyl-3,5-dimethylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one(0.150 g, 0.34 mmol) in 2N HCl was heated at reflux temperature for 3days. The reaction was cooled to room temperature, basified with 1NNaOH, and extracted with CH₂Cl₂. Purification by flash chromatography onsilica gel, eluting with 0% to 15% MeOH/CH₂Cl₂, followed by furtherpurification, eluting with 30% to 100% of 92:7:1 CHCl₃/MeOH/concentratedNH₄OH, afforded the title compound (0.040 g, 30%) as a white solid. ¹HNMR (300 MHz, DMSO-d₆): δ 11.98 (br s, 1H), 8.08 (d, J=9.0 Hz, 2H), 7.00(d, J=9.0 Hz, 2H), 6.68 (d, J=2.3 Hz, 1H), 6.46 (d, J=2.3 Hz, 1H), 3.88(s, 3H), 3.83 (s, 3H), 3.73-3.76 (m, 2H), 2.78-2.81 (m, 2H), 2.19-2.26(m, 2H), 1.03 (d, J=6.2 Hz, 6H). ESI MS m/z 395 [M+H]⁺.

Example 38. Preparation of2-(4-(4-Acetyl-3-methylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

To a solution of 4-fluorobenzaldehyde (2.0 g, 16.1 mmol) in DMF (10 mL)was added 2-methylpiperazine (1.9 g, 19.3 mmol) and K₂CO₃ (2.7 g, 19.3mmol). The reaction was heated at 120° C. for 6 hours, diluted with H₂O,and extracted with EtOAc. The organics were washed with brine, driedover anhydrous Na₂SO₄, filtered, and concentrated in vacuo, to afford4-(3-methylpiperazin-1-yl)benzaldehyde (2.3 g, 69%): ¹H NMR (300 MHz,CDCl₃): δ 9.77 (s, 1H), 7.75 (d, J=9.0 Hz, 2H), 6.90 (d, J=9.0 Hz, 2H),3.67-3.83 (m, 2H), 3.07-3.18 (m, 1H), 2.81-3.06 (m, 3H), 2.50-2.62 (m,1H), 1.46-1.73 (br s, 1H), 1.15 (d, J=6.3 Hz, 3H). ESI MS m/z 205[M+H]⁺.

A solution of 4-(3-methylpiperazin-1-yl)benzaldehyde (1.0 g, 4.89 mmol)in methylene chloride (15 mL) was cooled to 0° C. and treated with Et₃N(0.68 mL, 4.89 mmol), followed by acetyl chloride (0.34 mL, 4.89 mmol).The resulting solution was stirred at 0° C. for 20 minutes and thenconcentrated in vacuo. The material was purified by flash chromatographyon silica gel, eluting with 0% to 5% of EtOAc/CH₂Cl₂, to afford4-(4-acetyl-3-methylpiperazin-1-yl)benzaldehyde (0.88 g, 73%).

To a solution of 4-(4-acetyl-3-methylpiperazin-1-yl)benzaldehyde (0.400g, 1.62 mmol) in DMA (15 mL) was added 2-amino-4,6-dimethoxybenzamide(0.349 g, 1.78 mmol), NaHSO₃ (0.201 g, 1.94 mmol) and p-TsOH (0.030 g,0.16 mmol). The resulting solution was heated to 155° C. for 5 hours.The mixture was cooled to room temperature, diluted with water,extracted with CH₂Cl₂, washed with brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The material was purified by flash chromatographyon silica gel, eluting with 50% to 100% of 92:7:1CHCl₃/MeOH/concentrated NH₄OH in CH₂Cl₂, to afford the title compound(0.150 g, 21%). ¹H NMR (300 MHz, DMSO-d₆): mixture of rotamers δ 11.57(s, 1H), 8.10 (d, J=8.9 Hz, 2H), 6.90-7.14 (m, 2H), 6.68 (s, 1H), 6.46(s, 1H), 4.42-4.75 (m, 0.5H), 4.03-4.42 (m, 1H), 3.61-4.02 (m, 8H),3.41-3.60 (m, 1H), 2.85-3.13 (m, 2H), 2.63-2.85 (m, 0.5H), 1.88-2.13 (m,3H), 1.04-1.31 (m, 3H). ESI MS m/z 423 [M+H]⁺.

Example 39. Preparation ofN-(1-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)pyrrolidin-3-yl)acetamide

A solution of2-(4-(3-aminopyrrolidin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one(0.150 g, 0.41 mmol) in CH₂Cl₂ (10 mL) was treated with Et₃N (0.114 mL,0.82 mmol), cooled to 0° C., and acetyl chloride (0.029 mL, 0.41 mmol)was added. The mixture was stirred for 2 hours at room temperature,concentrated, and purified by flash chromatography on silica gel,eluting with 1:1 CH₂Cl₂/92:7:1 CHCl₃/MeOH/concentrated NH₄OH to 100%92:7:1 CHCl₃/MeOH/concentrated NH₄OH. The mixture was further purifiedby flash chromatography on silica gel, eluting with 9:1 methylenechloride/methanol, to afford the title compound (0.130 g, 78%) as ayellow solid. ¹H NMR (300 MHz, DMSO-d₆): δ 11.67 (s, 1H), 8.18 (d, J=6.8Hz, 1H), 8.14 (d, J=6.8 Hz, 2H), 6.66 (d, J=2.3 Hz, 1H), 6.60 (d, J=9.0Hz, 2H), 6.44 (d, J=2.3 Hz, 1H), 4.36-4.39 (m, 1H), 3.88 (s, 3H), 3.83(s, 3H), 3.13-3.59 (m, 5H), 2.15-2.22 (m, 1H), 1.90-1.94 (m, 1H), 1.82(s, 3H). ESI MS m/z 409 [M+H]⁺.

Example 40. Preparation of2-(4-(4-Isopropylpiperazin-1-yl)phenyl)-8-methoxyquinazolin-4(3H)-one

To a solution of 2-amino-3-methoxy benzoic acid (2.0 g, 11.90 mmol) inTHF (30 mL) was added EDCI (2.7 g, 14.3 mmol), HOBt (1.9 g, 14.3 mmol)and NMM (1.6 mL, 14.3 mmol). The reaction was stirred at roomtemperature for 2 hours and then NH₄OH (1 mL) in H₂O (1 mL) was added.After stirring overnight, the reaction was diluted with H₂O andextracted with CH₂Cl₂. The organics were washed with brine, dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo. The solids weresuspended in Et₂O and filtered off to afford 2-amino-3-methoxybenzamide(1.1 g, 56%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.71 (br s, 1H), 7.19 (d,J=8.1 Hz, 1H), 7.08 (br s, 1H), 6.87 (d, J=7.1 Hz, 1H), 6.45-6.53 (m,1H), 6.26 (br s, 2H), 3.78 (s, 3H).

A mixture of 4-(4-isopropylpiperazin-1-yl)benzaldehyde (0.562 g, 2.40mmol), NaHSO₃ (0.310 g, 2.90 mmol), and p-TsOH (0.046 g, 0.24 mmol) wasadded to a solution of 2-amino-3-methoxybenzamide (0.400 g, 2.40 mmol)in DMA (15 mL). The reaction was stirred at 120° C. overnight. Themixture was diluted with H₂O and saturated NaHCO₃ and extracted withCH₂Cl₂. The organics were washed with brine, dried (Na₂SO₄), filteredand concentrated in vacuo. Purification by flash chromatography onsilica gel eluting with 0% to 10% MeOH/CH₂Cl₂ afforded the titlecompound (0.140 g, 15%). ¹H NMR (300 MHz, DMSO-d₆): δ 12.27 (s, 1H),8.10 (d, J=8.9 Hz, 2H), 7.64-7.70 (m, 1H), 7.31-7.39 (m, 2H), 7.03 (d,J=9.1 Hz, 2H), 3.93 (s, 3H), 3.27-3.32 (m, 4H), 2.64-2.75 (m, 1H),2.56-2.59 (m, 4H), 1.00 (d, J=6.6 Hz, 6H). ESI MS m/z 379 [M+H]⁺.

Example 41. Preparation ofN-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)-N-isopropylacetamide

To the solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.0 g,25.09 mmol) in methanol (35 mL) was added isopropylamine (1.07 mL, 12.54mmol), acetic acid (0.94 mL, 16.30 mmol) and sodium cyanoborohydride(1.0 g, 16.30 mmol). The resulting solution was stirred at roomtemperature for 1 hour, then quenched with water. The solution wasconcentrated in vacuo and redissolved in ethyl ether. The organics wereextracted with 0.1 N HCl. The aqueous extracts were basified with 1 NNaOH (pH>8) and extracted with ethyl ether. The organic extracts weredried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo, toafford tert-butyl 4-(isopropylamino)piperidine-1-carboxylate (1.2 g,41%) as a clear liquid.

To a 0° C. solution of tert-butyl4-(isopropylamino)piperidine-1-carboxylate (1.2 g, 5.19 mmol) in CH₂Cl₂(18 mL) was added Et₃N (1.44 mL, 10.38 mmol) followed by acetyl chloride(0.55 mL, 7.78 mmol). The resulting solution was stirred for 2.5 hours,then concentrated in vacuo. The material was purified by flashchromatography on silica gel, eluting with 0% to 5% of EtOAc/CH₂Cl₂, toafford tert-butyl 4-(N-isopropylacetamido)piperidine-1-carboxylate (0.88g, 59%).

A solution of tert-butyl4-(N-isopropylacetamido)piperidine-1-carboxylate (0.880 g, 3.09 mmol) inhydrogen chloride (4.0 M solution in 1,4-dioxane, 10 mL) was stirred atroom temperature overnight. The resulting solution was concentrated invacuo, basified with aqueous saturated NaHCO₃, and extracted with EtOAc.The organics were dried (Na₂SO₄), filtered, and concentrated in vacuo.The material was purified by flash chromatography on silica gel, elutingwith 50% to 100% of 92:7:1 CHCl₃/MeOH/concentrated NH₄OH in CH₂Cl₂. Theresidue was further purified by flash chromatography on silica gel,eluting with 100% of 92:7:1 CHCl₃/MeOH/concentrated NH₄OH, to affordN-Isopropyl-N-(piperidin-4-yl)acetamide hydrogen chloride (0.260 g, 45%)as a clear liquid.

To a solution of N-isopropyl-N-(piperidin-4-yl)acetamide hydrogenchloride (0.260 g, 1.41 mmol) in DMF (5 mL) was added4-fluorobenzaldehyde (0.18 mL, 1.69 mmol) and K₂CO₃ (0.233 g, 1.69mmol). The resulting solution was heated to 120° C. overnight, andcooled. The cooled solution was diluted with water and extracted withCH₂Cl₂. The organics were washed with brine, dried over anhydrousNa₂SO₄, filtered, and concentrated in vacuo. The material was purifiedby flash chromatography on silica gel, eluting with 0% to 5%MeOH/CH₂Cl₂, to affordN-(1-(4-formylphenyl)piperidin-4-yl)-N-isopropylacetamide (0.290 g,71%).

To a solution ofN-(1-(4-formylphenyl)piperidin-4-yl)-N-isopropylacetamide (0.300 g, 1.04mmol) in DMA (10 mL) was added 2-amino-4,6-dimethoxybenzamide (0.204 g,1.04 mmol), NaHSO₃ (0.129 g, 1.24 mmol) and p-TsOH (0.019 g, 0.10 mmol).The resulting solution was heated to 155° C. overnight and then cooledto room temperature. The solution was diluted with water, extracted withCH₂Cl₂, washed with brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated in vacuo. The material was purified by flash chromatographyon silica gel eluting, with 30% to 100% of 92:7:1CHCl₃/MeOH/concentrated NH₄OH in CH₂Cl₂, to afford the title compound(0.100 g, 20%). ¹H NMR (300 MHz, DMSO-d₆): mixture of rotamers δ 11.66(s, 1H), 8.07 (d, J=8.3 Hz, 2H), 6.89-7.15 (m, 2H), 6.67 (s, 1H), 6.46(s, 1H), 3.90-4.11 (m, 3H), 3.88 (s, 3H), 3.83 (s, 3H), 2.80-3.02 (m,2H), 2.39-2.66 (m, 1H), 1.92-2.06 (m, 3H), 1.63-1.82 (m, 2H), 1.32-1.47(m, 1H), 1.21-1.32 (m, 3H), 1.08-1.21 (m, 4H). ESI MS m/z 463 [M−H]⁻.

Example 42. Preparation of5-Chloro-2-(4-(4-isopropylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one

A solution of 2-amino-6-chlorobenzamide (0.314 g, 1.85 mmol) and4-(4-isopropylpiperazin-1-yl)benzaldehyde (0.430 g, 1.85 mmol) in DMA(25 mL) were treated with p-TsOH (0.035 g, 0.185 mmol) and NaHSO₃ (0.212g, 2.04 mmol), and the mixture was heated at 140° C. for 18 hours. Then,the mixture was cooled, diluted with CH₂Cl₂ (200 mL), and washed withsaturated NaHCO₃ (100 mL). The organic phase was dried over anhydrousMgSO₄, filtered, concentrated, and purified by silica gelchromatography, eluting with 1:1 CH₂Cl₂/92:7:1 CHCl₃/MeOH/concentratedNH₄OH to 100% 92:7:1 CHCl₃/MeOH/concentrated NH₄OH to 100% 6:3:1CHCl₃/MeOH/concentrated NH₄OH. The resulting solids wererechromatographed with 9:1 CH₂Cl₂/MeOH to afford the title compound as awhite solid. ¹H NMR (300 MHz, DMSO-d₆): δ 12.24 (br s, 1H), 8.11 (d,J=8.8 Hz, 2H), 7.66-7.71 (m, 1H), 7.59 (d, J=7.9 Hz, 1H), 7.42 (d, J=7.4Hz, 1H), 7.03 (d, J=8.6 Hz, 2H), 3.28-3.34 (m, 4H), 2.64-2.73 (m, 1H),2.55-2.59 (m, 4H), 1.01 (d, J=6.4 Hz, 6H). ESI MS m/z 383 [M+H]⁺.

Example 43. Preparation of2-(4-((3R,5S)-4-Isopropyl-3,5-dimethylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

To a mixture of 4-(3,5-dimethylpiperazin-1-yl)benzaldehyde (1.0 g, 4.6mmol) and K₂CO₃ (1.3 g, 9.2 mmol) in CH₃CN (10 mL) was added2-iodopropane (2.3 mL, 22.9 mmol) and the reaction was stirred at refluxtemperature overnight. Additional 2-iodopropane (2.3 mL, 22.9 mmol) andK₂CO₃ (1.3 g, 9.2 mmol) were added and the reaction was continued toreflux overnight. The mixture was concentrated in vacuo and purified byflash chromatography on silica gel, eluting with 1% to 10% MeOH/CH₂Cl₂,to afford 4-(4-isopropyl-3,5-dimethylpiperazin-1-yl)benzaldehyde (0.550g, 46%).

A mixture of 4-(4-isopropyl-3,5-dimethylpiperazin-1-yl)benzaldehyde(0.400 g, 1.50 mmol), NaHSO₃ (0.195 g, 1.80 mmol), and p-TsOH (0.030 g,0.15 mmol) was added to a solution of 2-amino-4,6-dimethoxybenzamide(0.400 g, 2.40 mmol) in DMA (10 mL). The reaction was stirred at 140° C.for 4 hours, then at room temperature overnight. The mixture was dilutedwith H₂O and extracted with CH₂Cl₂. The organics were washed with brine,dried (Na₂SO₄), filtered, and concentrated in vacuo. Purification byflash chromatography on silica gel, eluting with 1% to 10% MeOH/CH₂Cl₂,followed by reverse-phase chromatography, eluting with 10% to 90% CH₃CNin H₂O, afforded the title compound (0.114 g, 17%). ¹H NMR (300 MHz,DMSO-d₆): δ 11.68 (s, 1H), 8.09 (d, J=8.9 Hz, 2H), 6.78 (d, J=9.0 Hz,2H), 6.66 (s, 1H), 6.44 (s, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.41-3.44(m, 2H), 3.11-3.23 (m, 5H), 1.00-1.03 (m, 12H). ESI MS m/z 437 [M+H]⁺.

Example 44. Preparation of5,7-Dimethoxy-2-(4-(piperidin-4-yl)phenyl)quinazolin-4(3H)-one

To a solution of tert-butyl4-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidine-1-carboxylate(0.210 g, 0.45 mmol) in 1,4-dioxane (2 mL) was added 4M HCl in1,4-dioxane (1 mL). The resulting solution was stirred at roomtemperature for 5 hours. Then, the mixture was concentrated in vacuo andthe resulting material was purified by flash chromatography on silicagel, eluting with 0% to 10% of MeOH/CH₂Cl₂. The residue was furtherpurified by flash chromatography on silica gel, eluting with 100% of92:7:1 CHCl₃/MeOH/concentrated NH₄OH followed by 100% of 6:3:1CHCl₃/MeOH/concentrated NH₄OH, to afford the title compound (0.030 g,18%). ¹H NMR (300 MHz, DMSO-d₆): δ 8.11 (d, J=8.3 Hz, 2H), 7.37 (d,J=8.2 Hz, 2H), 6.73 (s, 1H), 6.53 (s, 1H), 3.89 (s, 3H), 3.85 (s, 3H),2.92-3.20 (m, 2H), 2.56-2.81 (m, 3H), 2.35-2.57 (m, 2H), 1.67-1.88 (m,2H), 1.38-1.67 (m, 2H). ESI MS m/z 366 [M+H]⁺.

Example 45. Preparation of5,7-Dimethoxy-2-(4-(3-(methylamino)pyrrolidin-1-yl)phenyl)quinazolin-4(3H)-one

A mixture ofN-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)pyrrolidin-3-yl)-N-methylacetamide(0.500 g, 1.18 mmol) and 2 N HCl (80 mL) was heated at 100° C. for 4hours, cooled, basified to pH 9, extracted with CH₂Cl₂ (2×200 mL), dried(MgSO₄), filtered, and concentrated. The residue was purified by flashchromatography on silica gel, eluting with 1:1 CH₂Cl₂/92:7:1CHCl₃/MeOH/concentrated NH₄OH to 100% 92:7:1 CHCl₃/MeOH/concentratedNH₄OH to 6:3:1 CHCl₃/MeOH/concentrated NH₄OH, to afford the titlecompound (0.210 g, 47%) as a pale yellow solid. ¹H NMR (300 MHz,DMSO-d₆): δ 11.65 (br s, 1H), 8.08 (d, J=8.7 Hz, 2H), 6.65 (s 1H), 6.55(d, J=7.8 Hz, 2H), 6.43 (s, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.46-3.49(m, 1H), 3.38-3.42 (m, 1H), 3.26-3.28 (m, 2H), 3.07-3.10 (m, 1H), 2.31(s, 3H), 2.08-2.11 (m, 1H), 1.81-1.84 (m, 1H). ESI MS m/z 381 [M+H]⁺.

Example 46. Preparation of Tert-butyl4-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidine-1-carboxylate

A solution of 2-(4-bromophenyl)-5,7-dimethoxyquinazolin-4(3H)-one (1.1g, 3.23 mmol), K₂CO₃ (1.3 g, 9.69 mmol), PdCl₂(dppf) (0.261 g, 0.32mmol) and tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(1.0 g, 3.23 mmol) in DMF (50 mL) was heated to 110° C. overnight. Theresulting solution was concentrated in vacuo and the material waspurified twice by flash chromatography on silica gel, eluting with 0% to5% of MeOH/CH₂Cl₂. The residue was further purified by flashchromatography on silica gel, eluting with 10% to 50% of EtOAc/CH₂Cl₂,to afford tert-butyl4-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate(0.030 g, 49%) as a light yellow solid.

A solution of tert-butyl4-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate(0.160 g, 0.34 mmol) in EtOH (10 mL) and HOAc (5 mL) was purged withnitrogen, and 10% Pd/C (0.016 g) was added. The mixture was stirredunder 1 atmosphere of hydrogen overnight. Then, the solution wasfiltered through Celite, with MeOH washings, and the filtrate wasconcentrated in vacuo. The material was purified by flash chromatographyon silica gel, eluting with 30% to 70% of 92:7:1 CHCl₃/MeOH/concentratedNH₄OH in CH₂Cl₂, to afford the title compound (0.160 g, 100%). ¹H NMR(300 MHz, DMSO-d₆): δ 11.91 (s, 1H), 8.11 (d, J=8.3 Hz, 2H), 7.40 (d,J=8.5 Hz, 2H), 6.73 (s, 1H), 6.53 (s, 1H), 4.00-4.22 (m, 2H), 3.89 (s,3H), 3.85 (s, 3H), 2.65-2.97 (m, 3H), 1.68-1.88 (m, 2H), 1.48-1.68 (m,2H), 1.42 (s, 9H). ESI MS m/z 466 [M+H]⁺.

Example 47. Preparation ofN-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)pyrrolidin-3-yl)-N-methylacetamide

A solution of 4-fluorobenzaldehyde (2.01 g, 16.2 mmol) andN-methyl-N-(pyrrolidin-3-yl)acetamide (1.92 g, 13.5 mmol) in DMF (20 mL)was treated with K₂CO₃ (2.24 g, 16.2 mmol). The mixture was heated at120° C. under nitrogen for 18 hours, cooled to room temperature, dilutedwith ethyl acetate (150 mL), washed with brine, dried (Na₂SO₄),filtered, and concentrated. The residue was purified by flashchromatography on silica gel, eluting with 100% ethyl acetate to 10%methanol/ethyl acetate, to affordN-(1-(4-formylphenyl)pyrrolidin-3-yl)-N-methylacetamide.

A solution of 2-amino-4,6-dimethoxybenzamide (0.797 g, 4.07 mmol) andN-(1-(4-formylphenyl)pyrrolidin-3-yl)-N-methylacetamide (1.0 g, 4.07mmol) in DMA (75 mL) was treated with NaHSO₃ (0.466 g, 4.5 mmol) andp-TsOH (0.078 g, 0.41 mmol). The mixture was heated at 150° C. for 15hours, cooled to room temperature, diluted with CH₂Cl₂ (200 mL), andwashed with saturated NaHCO₃ (100 mL) and water (200 mL). The organicphase was dried over anhydrous MgSO₄, filtered, and concentrated. Theresidue was purified by flash chromatography on silica gel, eluting with1:1 CH₂Cl₂/92:7:1 CHCl₃/MeOH/concentrated NH₄OH to 100% 92:7:1CHCl₃/MeOH/concentrated NH₄OH, to afford the title compound (1.5 g, 88%)as a light brown solid. ¹H NMR (300 MHz, DMSO-d₆): δ 11.68 (s, 1H), 8.10(d, J=8.8 Hz, 2H), 6.55-6.67 (m, 3H), 6.44 (d, J=2.2 Hz, 1H), 4.67-5.22(m, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.43-3.60 (m, 2H), 3.22-3.26 (m,2H), 2.76-2.89 (m, 3H), 1.91-2.27 (m, 5H). ESI MS m/z 423 [M+H]⁺.

Example 48. Preparation of2-(4-(4-(Isopropylamino)piperidin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

A solution ofN-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)-N-isopropylacetamide(0.130 g, 0.27 mmol) in 2 N HCl (8 mL) was heated to reflux and stirredovernight. The resulting solution was cooled to room temperature,basified with 2 N NaOH (pH 14), and extracted with CH₂Cl₂. The solutionwas concentrated in vacuo and the residue was purified by flashchromatography on silica gel, eluting with 30% to 100% of 92:7:1CHCl₃/MeOH/concentrated NH₄OH in CH₂Cl₂, to afford the title compound(0.060 g, 52%). ¹H NMR (300 MHz, DMSO-d₆): δ 8.07 (d, J=9.0 Hz, 2H),6.99 (d, J=9.1 Hz, 2H), 6.67 (s, 1H), 6.46 (s, 1H), 3.75-3.95 (m, 8H),2.81-2.99 (m, 3H), 2.69-2.79 (m, 1H), 1.79-1.92 (m, 2H), 1.14-1.37 (m,3H), 0.97 (d, J=6.1 Hz, 6H). ESI MS m/z 423 [M+H]⁺.

Example 49. Preparation of5,7-Dimethoxy-2-(4-(3-methylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one

A solution of2-(4-(4-acetyl-3-methylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one(0.340 g, 0.80 mmol) in 2 N HCl (5 mL) was heated to reflux and stirredfor 3 days. Then, the resulting solution was cooled to room temperature,basified with 2 N NaOH, extracted with CH₂Cl₂, and concentrated invacuo. The material was purified by flash chromatography on silica gel,eluting with 50% to 100% of 92:7:1 CHCl₃/MeOH/concentrate NH₄OH inCH₂Cl₂, to afford the title compound (0.03 g, 9%). ¹H NMR (300 MHz,DMSO-d₆): δ 10.76 (s, 1H), 8.08 (d, J=8.9 Hz, 2H), 6.99 (d, J=9.1 Hz,2H), 6.67 (s, 1H), 6.46 (s, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.62-3.79(m, 2H), 2.90-3.04 (m, 1H), 2.57-2.85 (m, 4H), 2.20-2.39 (m, 1H), 1.03(d, J=6.3 Hz, 3H). ESI MS m/z 381 [M+H]⁺.

Example 50. Preparation ofN-Benzyl-N-(1-(5-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperidin-4-yl)acetamide

To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (10.0 g, 50.2mmol) and benzylamine (2.7 mL, 25.1 mmol) in MeOH (30 mL) was added HOAc(1.9 mL, 32.6 mmol), followed by NaCNBH₃ (2.0 g, 32.6 mmol) and thereaction was stirred at room temperature overnight. The resultingmixture was quenched with H₂O (5 mL) and concentrated in vacuo. Theresidue was diluted with 0.1 N HCl and washed with Et₂O. The aqueouslayer was then basified with 2 N NaOH and extracted with Et₂O. Theorganics were washed with brine, dried over anhydrous Na₂SO₄, filtered,and concentrated in vacuo, to afford tert-butyl4-(benzylamino)piperidine-1-carboxylate (8.1 g, 56%).

To a solution of tert-butyl 4-(benzylamino)piperidine-1-carboxylate (8.1g, 28.0 mmol) and Et₃N (7.8 mL, 56.0 mmol) in CH₂Cl₂ (100 mL) was addedacetyl chloride (2.4 mL, 33.5 mmol) and the reaction was stirred at roomtemperature overnight, then concentrated in vacuo. Purification by flashchromatography on silica gel, eluting with 30% to 60% EtOAc/CH₂Cl₂,afforded tert-butyl 4-(N-benzylacetamido)piperidine-1-carboxylate (9.3g, 99%).

A solution of tert-butyl 4-(N-benzylacetamido)piperidine-1-carboxylate(9.3 g, 28.0 mmol) in dioxane (20 mL) and 4 M HCl/dioxane (14.0 mL, 56.0mmol) was stirred at room temperature overnight and then concentrated invacuo. The residue was basified with 2 N NaOH and extracted with EtOAc.The organics were washed with brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo, to afford N-benzyl-N-(piperidin-4-yl)acetamide(4.4 g, 67%).

To a solution of N-benzyl-N-(piperidin-4-yl)acetamide (1.5 g, 6.3 mmol)and 2-(6-chloropyridin-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one (1.0 g,3.2 mmol) in DMF (15 mL) was added K₂CO₃ (0.875 g, 6.3 mmol) and thereaction was heated at reflux temperature overnight. The resultingmixture was concentrated in vacuo and purified by flash chromatographyon silica gel, eluting with 1% to 10% MeOH/CH₂Cl₂, to afford the titlecompound (0.500 g, 30%) as a white solid. ¹H NMR (300 MHz, DMSO-d₅): δ11.84 (s, 1H), 8.86 (s, 1H), 8.22 (d, J=9.2 Hz, 1H), 7.33-7.37 (m, 1H),7.14-7.27 (m, 4H), 6.88-6.96 (m, 1H), 6.66 (d, J=1.5 Hz, 1H), 6.46 (d,J=1.5 Hz, 1H), 4.44-4.58 (m, 4.5H), 4.10-4.20 (m, 0.5H), 3.87 (s, 3H),3.83 (s, 3H), 2.86-2.98 (m, 2H), 2.25 (s, 1.5H), 1.95 (s, 1.5H),1.45-1.77 (m, 4H). ESI/APCI MS m/z 514 [M+H]⁺.

Example 51. Preparation of2-(6-(4-(Benzylamino)piperidin-1-yl)pyridin-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one

A solution ofN-benzyl-N-(1-(5-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperidin-4-yl)acetamide(0.200 g, 0.39 mmol) in 2 N HCl (15 mL) was refluxed for 3 days. Theresulting mixture was basified with 2 N NaOH and extracted with CH₂Cl₂.The organics were washed with brine, dried over anhydrous Na₂SO₄,filtered, and concentrated in vacuo. Purification by flashchromatography on silica gel, eluting with 10% to 100% of 92:7:1CHCl₃/MeOH/concentrated NH₄OH in CH₂Cl₂, afforded the title compound(0.110 g, 60%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 11.11 (brs, 1H), 8.89 (d, J=2.3 Hz, 1H), 8.22-8.26 (m, 1H), 7.28-7.37 (m, 4H),7.18-7.23 (m, 1H), 6.91 (d, J=7.2 Hz, 1H), 6.67 (d, J=2.2 Hz, 1H), 6.46(d, J=2.2 Hz, 1H), 4.27-4.31 (m, 2H), 3.88 (s, 3H), 3.83 (s, 3H), 3.76(s, 2H), 3.00-3.11 (m, 2H), 2.62-2.69 (m, 1H), 1.88-1.91 (m, 2H),1.25-1.31 (m, 2H). ESI MS m/z 472 [M+H]⁺.

Example 52. Preparation of4-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperazine-1-carbaldehyde

A mixture of methyl formate (75 mL) and5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.300 g,0.82 mmol) was heated at reflux for 48 hours. The mixture wasconcentrated, and purified by silica gel chromatography, eluting with1:1 CH₂Cl₂/92:7:1 CHCl₃/MeOH/concentrated NH₄OH, to afford the titlecompound (0.320 g, 99%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆): δ11.79 (br s, 1H), 8.10-8.19 (m, 3H), 7.06 (d, J=9.1 Hz, 2H), 6.69 (d,J=2.3 Hz, 1H), 6.48 (d, J=2.3 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H),3.46-3.59 (m, 4H), 3.32-3.38 (m, 4H). APCI MS m/z 393 [M−H]⁻.

Example 53. Preparation of5,7-Dimethoxy-2-(4-(4-oxopiperidin-1-yl)phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one

To a solution of2-[4-(4-hydroxy-piperazin-1-yl)-phenyl]-5,7-dimethoxy-3H-pyrido[2,3-d]pyrimidin-4-one(160 mg, 0.418 mmol) in DMSO (4.0 mL),1,2-benziodexol-3(1H)-one-1-hydroxy-1-oxide (IBX) (178 mg, 0.635 mmol)was added and the reaction mixture was kept at 50° C. for 16 hours.Water was added and the precipitated solid was filtered to give crudeproduct, which was purified by column chromatography (silica gel 230-400mesh; eluting with 3% methanol in dichloromethane) to obtain the titlecompound as a yellow solid. Yield: 0.70 g (44.0%). MP>350° C. ¹H NMR(400 MHz, CDCl₃): δ 12.15 (s, 1H), 8.18 (d, J=9.2 Hz, 2H), 7.02 (d,J=9.2 Hz, 2H), 6.33 (s, 1H), 3.95 (s, 3H), 3.90 (s, 3H), 3.77 (t, J=6.4Hz, 4H), 2.45 (t, J=6.4 Hz, 4H).

Example 54. Preparation of2-(2-(Hydroxymethyl)-1H-indol-5-yl)-5,7-dimethoxyquinazolin-4(3H)-one

To a solution of N-(4-formyl-phenyl)-acetamide (1.25 g, 7.67 mmol) intrifluoroacetic acid (70 mL) was slowly addedthallium(III)trifluoroacetate (5.00 g, 9.20 mmol). The reaction mixturewas stirred at room temperature for 30 minutes. Then, a solution ofsodium iodide (1.19 g, 7.95 mmol) in water (10 mL) was added slowly. Thecolor changed to dark purple and a lot of solid was formed. Stirringcontinued at room temperature for 16 hours. Solvent was evaporated tohalf of the volume, and water (50 mL) was added. The pH was adjusted toapproximately 13 with 4 N NaOH solution. The mixture was extracted withethyl acetate (2×100 mL). The organic phase was dried over anhydrousNa₂SO₄ and concentrated on a rotary evaporator. The solid obtained waswashed with ethyl acetate (2×5 mL), ether (2×10 mL), and dried undervacuum to give N-(4-formyl-2-iodo-phenyl)-acetamide as an off-whitesolid. Yield: 0.760 g (34%).

To a degassed solution of N-(4-formyl-2-iodo-phenyl)-acetamide (0.760 g,2.63 mmol) in anhydrous DMF (20 mL) were addedbis(triphenylphosphine)palladium(II) dichloride (90 mg, 0.13 mmol),copper (I) iodide (0.03 g, 0.13 mmol), 1,1,3,3-tetramethyl guanidine(1.51 g, 13.1 mmol), and propargyl alcohol (0.210 g, 3.68 mmol). Thereaction mixture was stirred at room temperature for 2 hours and then at80° C. for 24 hours under nitrogen. Solvent was evaporated under reducedpressure. Water (100 mL) was added and the mixture was extracted withethyl acetate (200 mL). The organic phase was backwashed with water(2×100 mL), brine (100 mL), and dried over anhydrous Na₂SO₄. Solvent wasevaporated and crude compound was purified by the Simpliflash system(60% ethyl acetate in hexanes as eluent) to give2-hydroxymethyl-1H-indole-5-carbaldehyde as a pale yellow solid. Yield:0.10 g (22%).

To a solution of 2-hydroxymethyl-1H-indole-5-carbaldehyde (90 mg, 0.51mmol) and 2-amino-4,6-dimethoxy-benzamide (0.15 g, 0.77 mmol) inN,N-dimethylacetamide (5 mL) were added sodium hydrogen sulfite (58.5 wt%) (0.14 g, 0.77 mmol) and p-toluenesulfonic acid (20 mg, 0.10 mmol).The reaction mixture was stirred at 120° C. for 16 hours under nitrogen,cooled to room temperature, and concentrated under reduced pressure.Water (20 mL) was added. The separated solid was filtered, washed withwater (20 mL) and ether (20 mL), and dried under vacuum. Crude compoundwas purified by column chromatography (silica gel 230-400 mesh; 0-5%methanol in CH₂Cl₂ as eluent), to give the title compound as anoff-white solid. Yield: 0.06 g (33%). MP 264-265° C. ¹H NMR (400 MHz,DMSO-d₆): δ 11.85 (br s, 1H), 11.36 (s, 1H), 8.39 (s, 1H), 7.93 (dd,J=8.6 and 1.6 Hz, 1H), 7.44 (d, J=9.0 Hz, 1H), 6.73 (d, J=2.3 Hz, 1H),6.49 (d, J=2.4 Hz, 1H), 6.41 (s, 1H). 5.34 (t, J=5.8 Hz, 1H), 4.63 (d,J=5.5 Hz, 2H), 3.90 (s, 3H), 3.85 (s, 3H).

Example 55. Preparation of2-(2-(2-Hydroxyethyl)-1H-indol-5-yl)-5,7-dimethoxyquinazolin-4(3H)-one

To a stirred solution of 4-amino-3-iodo-benzoic acid methyl ester (11.1g, 40.0 mmol) in pyridine (80 mL) was added acetyl chloride (3.30 g,42.0 mmol) at 0° C. under nitrogen. Stirring continued at 0° C. for 30minutes. The ice-bath was removed, and stirring continued at roomtemperature for 16 hours. Pyridine was evaporated under reducedpressure. The residue was taken in ethyl acetate (300 mL). The organicphase was washed with 2 N aqueous HCl (200 mL), water (200 mL), brine(200 mL), and then dried over anhydrous Na₂SO₄. Removal of solvent gave4-acetylamino-3-iodo-benzoic acid methyl ester as a white solid. Yield:12.71 g (99%).

Lithium aluminium hydride (2.43 g, 64.1 mmol) was taken in a dry,three-necked, round bottom flask. Anhydrous THF (80 mL) was added andcooled to −10° C. A solution of 4-acetylamino-3-iodo-benzoic acid methylester (10.2 g, 32.0 mmol) in anhydrous THF (60 mL) was added dropwise at−10° C. over a period of 45 minutes under nitrogen. Stirring wascontinued at −10° C. for 1 hour. The reaction mixture was quenched withsaturated sodium sulfate aqueous solution. The reaction mixture was thenfiltered, and the filtrate was concentrated. The solid was washed withmethanol. The combined organic phases were dried over anhydrous Na₂SO₄.The solvent was evaporated. The crude compound was purified by theSimpliflash system (5% methanol in CH₂Cl₂ as eluent), to giveN-(4-hydroxymethyl-2-iodo-1-phenyl)-acetamide as a white solid. Yield:6.36 g (68%).

To a solution of IBX (0.93 g, 3.3 mmol) in dimethylsulfoxide (3.5 mL)was added N-(4-hydroxymethyl-2-iodo-phenyl)-acetamide (0.87 g, 3.0 mmol)and the reaction mixture was stirred at room temperature for 1 hour.Water (50 mL) was added and the solid was separated by filtration, andwashed with ethyl acetate (20 mL). The filtrate was collected andextracted with ethyl acetate (200 mL). The organic phase was washed withbrine (100 mL) and dried over anhydrous Na₂SO₄. Removal of solvent gaveN-(4-formyl-2-iodo-phenyl)-acetamide as a light brown solid. Yield: 0.82g (95%).

To a degassed solution of N-(4-formyl-2-iodo-phenyl)-acetamide (0.810 g,2.82 mmol) in DMF (25 mL) and triethylamine (5 mL) were addedPdCl₂(PPh₃)₂ (0.10 g, 0.14 mmol) and copper (I) iodide (0.16 g, 0.85mmol). A degassed solution of but-3-yn-1-ol (0.27 g, 0.29 mmol) in DMF(8 mL) and triethylamine (2 mL) was added at 80° C. over a period of 1hour under nitrogen. After the addition, the reaction mixture wasstirred at 80° C. for 4 hours, cooled to room temperature, andconcentrated under reduced pressure. The residue was diluted with water(100 mL) and extracted with ethyl acetate (200 mL). The organic phasewas washed with brine (100 mL) and dried over anhydrous Na₂SO₄. Removalof solvent gave N-[4-formyl-2-(4-hydroxy-but-1-ynyl)-phenyl]-acetamideas a brown solid. Crude yield: 0.85 g (100%). The crude material wasused in next step without further purification.

To a solution of N-[4-formyl-2-(4-hydroxy-but-1-ynyl)-phenyl]-acetamide(0.85 g, approximately 2.80 mmol) in THF (20 mL) was added a THFsolution of TBAF (6.0 mL, 6.0 mmol) and the reaction mixture was stirredat reflux for 36 hours under nitrogen and cooled to room temperature.Solvent was evaporated and the residue was taken in ethyl acetate (200mL). The organic phase was washed with water (2×100 mL), brine (100 mL)and dried over anhydrous Na₂SO₄. Solvent was evaporated; crude compoundwas purified by simpliflash system (50% ethyl acetate in hexanes aseluent) to give 2-(2-hydroxy-ethyl)-1H-indole-5-carbaldehyde as yellowsolid. Yield: 0.31 g (58% for two steps).

To a solution of 2-(2-hydroxy-ethyl)-1H-indole-5-carbaldehyde (0.300 g,1.58 mmol) and 2-amino-4,6-dimethoxy-benzamide (0.370 g, 1.90 mmol) inN,N-dimethylacetamide (5 mL) were added sodium hydrogen sulfite (58.5 wt%) (0.350 g, 1.90 mmol) and p-toluenesulfonic acid monohydrate (60 mg,0.32 mmol). The reaction mixture was stirred at 120° C. for 16 hoursunder nitrogen and cooled to room temperature. The solvent wasevaporated under reduced pressure. Water (20 mL) was added and the solidwas separated by filtration, washed with water (30 mL) and dried undervacuum. Crude compound was purified by the Simpliflash system (5:20:75methanol/ethyl acetate/CH₂Cl₂ as eluent) to give the title compound asan off-white solid. Yield: 0.22 g (38%). MP 237-238° C. ¹H NMR (400 MHz,DMSO-d₆): δ 11.83 (br s, 1H), 11.20 (s, 1H), 8.34 (s, 1H), 7.90 (d,J=8.2 Hz, 1H), 7.37 (d, J=8.6 Hz, 1H), 6.73 (d, J=1.9 Hz, 1H), 6.48 (d,J=1.9 Hz, 1H), 6.30 (s, 1H), 4.81 (t, J=5.1 Hz, 1H), 3.89 (s, 3H), 3.84(s, 3H), 3.75 (q, J=6.63 Hz, 2H), 2.89 (t, J=7.0 Hz, 2H).

Example 56. Preparation of5,7-Dimethoxy-2-(2-(pyrrolidin-1-ylmethyl)-1H-indol-5-yl)quinazolin-4(3H)-one

To a mixture of 5-bromo-1H-indole-2-carboxylic acid (1.0 g, 4.2 mmol),1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (1.1g, 5.9 mmol), 1-hydroxybenzotriazole hydrate (HOBt) (0.62 g, 4.6 mmol)in THF (20 mL) was added 4-methylmorpholine (NMM) (0.65 mL, 5.9 mmol).After 10 minutes, pyrrolidine (0.73 mL, 8.8 mmol) was added. The mixturewas stirred at room temperature under nitrogen for 17 hours. The solventwas removed under reduced pressure. Water was added, stirred for 0.5hours. The solid was filtered, washed with water, and dried in air toafford (5-bromo-1H-indol-2-yl)-pyrrolidin-1-yl-methanone as a paleyellow solid. Yield: 1.2 g (95%).

To a suspension of (5-bromo-1H-indol-2-yl)-pyrrolidin-1-yl-methanone(0.53 g, 1.8 mmol) in THF (50 mL) at 0° C. was slowly added lithiumaluminum hydride (0.20 g, 5.4 mmol). The mixture was stirred undernitrogen at 0° C. for a while and the cooling bath was allowed to warmto room temperature. The mixture was then stirred at room temperaturefor 17 hours. The reaction was quenched by careful, successive, dropwiseaddition of water (0.2 mL), 15% NaOH aqueous solution (0.2 mL), andwater (0.6 mL). The solid was filtered and washed with MeOH and CH₂Cl₂.The filtrate was concentrated to dryness, and dried under vacuum, togive 5-bromo-2-pyrrolidin-1-ylmethyl-1H-indole as a white solid. Yield:0.45 g (90%).

To a suspension of potassium hydride (30 wt % dispersion in mineral oil)(96 mg, 0.72 mmol) in ether (20 mL) at 0° C. was added5-bromo-2-pyrrolidin-1-ylmethyl-1H-indole (0.20 g, 0.72 mmol). Afterstirring for 30 minutes, the reaction mixture was cooled to −78° C., andt-BuLi solution (1.7 M in pentane; 0.93 mL, 1.58 mmol) was added. Themixture was stirred at −78° C. for 15 minutes, then at −20° C. forapproximately 3 min, and then it was cooled down to −78° C. again. DMFwas added. The mixture was stirred under nitrogen at −78° C. for a whileand the cooling bath was allowed to warm to room temperature. SaturatedNaHCO₃ aqueous solution (approximately 5 mL) was added. The mixture wasextracted with dichloromethane. The organic solution was dried overNa₂SO₄, and concentrated to dryness to afford a mixture of the desiredproduct and starting material, at about a 1:1 ratio, from the NMRspectrum. The crude product (approximately 0.2 g) was used for nextreaction without any further purification.

A mixture of 2-amino-4,6-dimethoxy-benzamide (0.20 g, 1.0 mmol), crude2-pyrrolidin-1-ylmethyl-1H-indole-5-carbaldehyde (0.23 g, 1.0 mmol),p-toluenesulfonic acid monohydrate (0.38 g, 2.0 mmol), and sodiumbisulfite (0.42 g, 4.0 mmol) in N,N-dimethylacetamide (5 mL) was stirredat 115° C. under N₂ for 17 hours and cooled to room temperature. Themixture was diluted with saturated Na₂CO₃ aqueous solution andconcentrated to dryness under reduced pressure. The residue was purifiedby column chromatography on silica gel, eluting with CH₂Cl₂:7.0 M NH₃ inMeOH (95:5), to afford the title compound as a yellow solid. Yield: 87mg (22%). MP 168-169.5° C. (decomposition). ¹H NMR (400 MHz, CDCl₃): δ9.05 (s, 1H), 8.22 (s, 1H), 7.85 (d, 1H), 7.43 (d, 1H), 6.84 (s, 1H),6.45 (s, 1H), 6.43 (s, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 3.81 (s, 2H),2.57 (m, 4H), 1.81 (m, 4H).

Example 57. Preparation of2-(3-(Hydroxymethyl)-1H-indazol-5-yl)-5,7-dimethoxyquinazolin-4(3H)-one

To a solution of sodium nitrite (20.0 g, 290.0 mmol) in THF (1000 mL)and water (50 mL) was added 1H-indole-5-carboxylic acid methyl ester(5.00 g, 28.5 mmol). The mixture was cooled to 0° C. and aqueous 6 N HCl(70 mL) was added dropwise at 0° C. After stirring for 3 days at roomtemperature, solvent was evaporated, and extracted with ethyl acetate(3×200 mL). The combined organic phase was washed brine (200 mL) anddried over anhydrous Na₂SO₄. The solvent was evaporated. The residue waspurified by the Simpliflash system (20-30% ethyl acetate in hexanes aseluent), to give 3-formyl-1H-indazole-5-carboxylic acid methyl ester asa yellow solid. Yield: 1.47 g, (25%).

To a solution of 3-formyl-1H-indazole-5-carboxylic acid methyl ester(0.37 g, 1.80 mmol) in anhydrous methanol (15 mL) was added sodiumborohydride (68 mg, 1.80 mmol) in small portions at 0° C. After theaddition, the reaction mixture was stirred at 0° C. for 30 minutes.Solvent was evaporated; water (100 mL) was added and the mixture wasextracted with ethyl acetate (150 mL). The organic phase was washed withbrine (100 mL) and dried over anhydrous Na₂SO₄. Solvent was evaporatedto give 3-hydroxymethyl-1H-indazole-5-carboxylic acid methyl ester as ayellow solid. Yield: 0.32 g (87%).

To a solution of 3-hydroxymethyl-1H-indazole-5-carboxylic acid methylester (0.32 g, 1.55 mmol) in a mixture of anhydrous dichloromethane andTHF (2:1, 60 mL) was added pyridinium p-toluene sulfonate (0.08 g, 0.31mmol) and then 3,4-dihydro-2H-pyran (0.19 g, 2.32 mmol) was added. Thereaction mixture was stirred at room temperature for 16 hours undernitrogen. Solvent was evaporated; water (100 mL) was added, and themixture was extracted with ethyl acetate (100 mL). The organic phase waswashed with brine (100 mL) and dried over anhydrous Na₂SO₄. Removal ofsolvent gave 3-(tetrahydro-pyran-2-yloxymethyl)-1H-indazole-5-carboxylicacid methyl ester as a yellow gummy material. Yield: 0.55 g (crude).This product was used in next step without further purification.

3-(Tetrahydro-pyran-2-yloxymethyl)-1H-indazole-5-carboxylic acid methylester (0.53 g crude, approximately 1.55 mmol) was taken in anhydrous THF(20 mL) and cooled to −10° C. A solution of lithium aluminium hydride(1.0 M solution in THF, 0.12 g, 3.10 mmol) was added drop-wise at −10°C. over a period of 15 minutes under nitrogen. Stirring continued at−10° C. for 1 hour and the reaction was then allowed to warm to roomtemperature and stirring continued at room temperature for 16 hours. Thereaction mixture was carefully quenched with saturated aq. saturatedammonium chloride solution (100 mL). Then, reaction mixture was dilutedwith ethyl acetate (100 mL). The organic phase was separated, washedwith brine (50 mL) and dried over anhydrous Na₂SO₄. Solvent wasevaporated to give[3-(tetrahydro-pyran-2-yloxymethyl)-1H-indazol-5-yl]-methanol as ayellow gummy material. Yield: 0.40 g (crude). This product was used inthe next step without further purification.

To a solution of[3-(tetrahydro-pyran-2-yloxymethyl)-1H-indazol-5-yl]-methanol (0.40 g,1.50 mmol) in DMSO (3 mL), IBX (0.42 g, 1.50 mmol) was added and thereaction mixture was stirred at room temperature for 3 hours undernitrogen. Water (50 mL) was added; the separated solid was filtered, andthe solid was washed with ethyl acetate (100 mL). The filtrate wascollected and the organic phase was separated, washed with brine (100mL), and dried over anhydrous Na₂SO₄. Removal of solvent gave3-(tetrahydro-pyran-2-yloxymethyl)-1H-indazole-5-carbaldehyde as anoff-white solid. Yield: 0.33 g (84%).

To a solution of3-(tetrahydro-pyran-2-yloxymethyl)-1H-indazole-5-carbaldehyde (0.32 g,1.23 mmol) and 2-amino-4,6-dimethoxy-benzamide (0.24 g, 1.23 mmol) inN,N-dimethylacetamide (10 mL) were added NaHSO₃ (58.5 wt %, 0.27 g, 1.48mmol) and p-toluenesulfonic acid monohydrate (0.05 g, 0.25 mmol); thereaction mixture was heated at 120° C. for 16 hours, then cooled to roomtemperature. Solvent was removed under reduced pressure. The residue wasdiluted with water (100 mL). The separated solid was filtered and washedwith water and dried under vacuum. The residue was purified by theSimpliflash system (0-5% methanol in CH₂Cl₂ as eluent) to give the titlecompound as an off-white solid. Yield: 30 mg (7%). MP 264-266° C. ¹H NMR(400 MHz, CD₃OD): δ 8.60 (s, 1H), 8.10 (d, J=8.98 Hz, 1H), 7.65 (d,J=8.98 Hz, 1H), 6.85 (d, J=1.95 Hz, 1H), 6.55 (d, J=1.95 Hz, 1H), 5.05(s, 2H), 3.96 (s, 6H).

Example 58. Preparation of5,7-Dimethoxy-2-(2-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-5-yl)quinazolin-4(3H)-one

To a stirred solution of 4-amino-3-iodo-benzoic acid methyl ester (11.1g, 40.0 mmol) in anhydrous pyridine (80 mL) was added acetyl chloride(3.30 g, 42.0 mmol) at 0° C. under nitrogen. Stirring was continued at0° C. for 30 minutes. The ice-bath was removed, and stirring continuedat room temperature for 16 hours. Pyridine was evaporated under reducedpressure. The residue was taken in ethyl acetate (300 mL). The organicphase washed with 2 N aqueous HCl (200 mL), water (200 mL), brine (200mL), and was dried over anhydrous Na₂SO₄. Removal of solvent gave4-acetylamino-3-iodo-benzoic acid methyl ester as a white solid. Yield:12.7 g (99%).

To but-3-yn-1-ol (40.0 g, 570.0 mmol) and 3,4-dihydro-2H-pyran (48.0 g,570.0 mmol) in anhydrous dichloromethane (350 mL) was added pyridiump-toluenesulfonate (0.45 g, 1.80 mmol). The mixture was stirred at roomtemperature for 16 hours. Solvent was evaporated, and the residue waspurified by vacuum distillation to give 2-but-3-ynyloxy-tetrahydro-pyranas a light yellow liquid. Yield: 60.0 g (68%).

To a degassed solution of 4-acetylamino-3-iodo-benzoic acid methyl ester(41.4 g, 130 mmol) in DMF (200 mL) and triethylamine (40 mL) were addedPdCl₂(PPh₃)₂ (3.99 g, 5.68 mmol) and copper (I) iodide (7.43 g, 39.0mmol). A degassed solution of 2-but-3-ynyloxy-tetrahydro-pyran (30.1 g,195 mmol) in DMF (100 mL) and triethylamine (20 mL) was added at 80° C.over a period of 1 hour under nitrogen. After the addition, the reactionmixture was stirred at 80° C. for 2 hours and then cooled to roomtemperature. Solvent was evaporated under reduced pressure. Ethylacetate (200 mL) was added. The solid was filtered, and washed withethyl acetate. The ethyl acetate solution was washed with brine, anddried over anhydrous Na₂SO₄. The organic phase was concentrated todryness, to afford 66.8 g crude4-acetylamino-3-[4-(tetrahydro-pyran-2-yloxy)-but-1-ynyl]-benzoic acidmethyl ester. This was used in next step without further purification.

A solution of crude4-acetylamino-3-[4-(tetrahydro-pyran-2-yloxy)-but-1-ynyl]-benzoic acidmethyl ester (33.4 g, approximately 65 mmol) in anhydrous THF (300 mL)was mixed with a 1.0 M solution of tetrabutylammonium fluoride in THF(110 mL, 110 mmol); the reaction mixture was stirred at 90° C. for 4hours under nitrogen, and then cooled to room temperature. Solvent wasevaporated and the residue was taken in ethyl acetate (300 mL). Theorganic phase was washed with water (300 mL), brine (200 mL), and driedover anhydrous Na₂SO₄. The solvent was evaporated and the crude compoundwas purified by column chromatography on silica gel, eluting withhexanes and ethyl acetate (3:1), to give2-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-indole-5-carboxylic acidmethyl ester. Yield: 14.9 g (76%).

Lithium aluminum hydride (3.38 g, 89.0 mmol) in anhydrous THF (100 mL)was cooled to −30° C.2-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-1H-indole-5-carboxylic acidmethyl ester (13.5 g, 44.5 mmol) in anhydrous THF (100 mL) was addeddropwise. The reaction mixture was stirred at −20° C. for 1 hour andthen at room temperature for 4 hours. The reaction mixture was cooled to0° C. and water (6 mL) was added slowly. Ammonium chloride solution (200mL) was added and extracted with ethyl acetate (2×200 mL). The organicphase was washed with water (100 mL), then brine (100 mL), and driedover anhydrous sodium sulfate. The solvent was evaporated to give{2-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-indol-5-yl}-methanol as awhite solid. Yield: 11.50 g (94%).

{2-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-1H-indol-5-yl}-methanol (11.5 g41.7 mmol) in anhydrous DMSO (45 mL) was added IBX (12.3 g, 43.8 mmol)and the reaction was stirred at room temperature for 2 hours. Thereaction mixture was poured into water (300 mL) and extracted with ethylacetate (300 mL), the organic phase was washed with water, then brine,and was purified by column chromatography on silica gel, eluting withdichloromethane, to give2-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-indole-5-carbaldehyde as awhite solid. Yield: 8.50 g (75%).

To a solution of 2-amino-4,6-dimethoxy-benzamide (6.10 g, 31.1 mmol) and2-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-indole-5-carbaldehyde (8.50 g,31.1 mmol) in N,N-dimethylacetamide (45 mL) was added NaHSO₃ (58.5 wt %,6.08 g, 34.2 mmol) and p-TSA (0.60 g, 3.11 mmol). The reaction mixturewas heated at 115° C. for 16 hours and then cooled to room temperature.N,N-dimethylacetamide was removed under reduced pressure, the residuewas diluted with water (50 mL) and the solid was collected and mixedwith dichloromethane (100 mL), ether (100 mL), and then filtered to givea mixture of5,7-dimethoxy-2-{2-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-indol-5-yl}-3H-quinazolin-4-oneand2-[2-(2-hydroxy-ethyl)-1H-indol-5-yl]-5,7-dimethoxy-3H-quinazolin-4-oneas a white solid, which was used in next step without furtherpurification. Yield: 7.50 g (crude).

A mixture of5,7-dimethoxy-2-{2-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-indol-5-yl}-3H-quinazolin-4-oneand2-[2-(2-hydroxy-ethyl)-1H-indol-5-yl]-5,7-dimethoxy-3H-quinazolin-4-one(7.50 g, 16.6 mmol) was dissolved in anhydrous methanol (60 mL). 1.0 MHCl in ether (42 mL) was added and the reaction was stirred at roomtemperature for 2 hours. The solid was filtered and the mother liquorwas evaporated to dryness and the residue was combined with the solid.Sodium bicarbonate solution (200 mL) was added and stirred for 1 hours.The separated solid was filtered and washed with cold water and driedunder vacuum to give2-[2-(2-hydroxy-ethyl)-1H-indol-5-yl]-5,7-dimethoxy-3H-quinazolin-4-oneas a white solid. Yield: 6.2 g (55%; 3 steps).

To a solution of2-[2-(2-hydroxy-ethyl)-1H-indol-5-yl]-5,7-dimethoxy-3H-quinazolin-4-one(6.20 g, 16.9 mmol) in anhydrous DMF (25 mL) was added carbontetrabromide (6.47 g, 19.5 mmol) and triphenylphosphine (5.11 g, 19.5mmol). The reaction mixture was stirred at 40° C. for 16 hours. DMF wasremoved under vacuum and water (150 mL) was added. The separated solidwas filtered and mixed with ether (150 mL) and heated for 10 minutes.The solid was filtered and dried under vacuum to give2-[2-(2-bromo-ethyl)-1H-indol-5-yl]-5,7-dimethoxy-3H-quinazolin-4-one asa white solid. Yield: 6.1 g (84%).

To a solution of2-[2-(2-bromo-ethyl)-1H-indol-5-yl]-5,7-dimethoxy-3H-quinazolin-4-one(6.10 g, 14.2 mmol) in anhydrous DMF (45 mL) was added pyrrolidine (6.07g, 85.4 mmol) and the reaction mixture was stirred at 45° C. for 15hours. DMF was removed under reduced pressure, the residue was taken inwater (150 mL), and stirred for 30 minutes. Separated solid wasfiltered, washed with water, and dried under vacuum. Crude compound waspurified by column chromatography (silica gel 230-400 mesh, eluting with5% 7.0 M ammonia in methanol solution in dichloromethane) to give thetitle compound as a white solid. Yield: 3.4 g (57%). MP 215-217° C. ¹HNMR (400 MHz, DMSO-d₆): δ 11.79 (s, 1H), 11.21 (s, 1H), 8.31 (s, 1H),7.88 (dd, J=8.8 and 1.6 Hz, 1H), 7.35 (d, J=8.8 Hz, 1H), 6.71 (d, J=2.4Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 6.28 (s, 1H), 3.87 (s, 3H), 3.83 (s,3H), 2.89 (t, J=8.0 Hz, 2H), 2.74 (t, J=8.0 Hz, 2H), 2.48 (m, 4H), 1.67(m, 4H).

Example 59. Preparation of2-(2-((Dimethylamino)methyl)-1H-indol-5-yl)-5,7-dimethoxyquinazolin-4(3H)-one

To a solution of 5-bromo-1H-indole-2-carboxylic acid (2.40 g, 10.0 mmol)in THF (100 mL) were added EDCI (2.11 g, 30.0 mmol), HOBt (1.49 g, 11.0mmol). The reaction mixture was stirred at room temperature for 10minutes. Then, a solution of N,N-dimethyl amine (2.0 M solution in THF,15 mL, 30.0 mmol) was added. The mixture was stirred for 16 hours atroom temperature. Solvent was evaporated, the residue was taken in ethylacetate (200 mL), and water (200 mL) was added. The organic phase wasseparated; the aqueous phase was extracted with ethyl acetate (200 mL).The combined organic phase was washed with water (100 mL), then brine(100 mL), and dried over anhydrous sodium sulfate. Solvent wasevaporated and dried under vacuum to give 5-bromo-1H-indole-2-carboxylicacid dimethylamide as an off-white solid. Yield: 2.56 g (96%).

5-Bromo-1H-indole-2-carboxylic acid dimethylamide (1.34 g, 5.00 mmol)was taken in anhydrous THF (50 mL) (suspension), and cooled to −20° C. Asolution of lithium aluminium hydride (1.0 M solution in THF, 10.0 mL,10.0 mmol) was added dropwise at −20° C. over a period of 15 minutesunder nitrogen, and allowed to warm to 10° C.; stirring was continued at10° C. for 1 hour. The reaction mixture was carefully quenched with aq.saturated ammonium chloride solution (10 mL). The reaction mixture wasdiluted with ethyl acetate (150 mL). The organic phase was separated,washed with water (100 mL), then brine (100 mL), and dried overanhydrous Na₂SO₄. Solvent was evaporated, to give(5-bromo-1H-indole-2-ylmethyl)-dimethyl amine as an off-white solid.Yield: 1.27 g (crude).

To a cold (0° C.) solution of potassium hydride (suspension in mineraloil, 0.79 g, 5.90 mmol) in anhydrous THF (60 mL) was added a solution of(5-bromo-1H-indole-2-ylmethyl)-dimethyl amine (1.24 g, 4.90 mmol) inanhydrous THF (20 mL) was added dropwise at 0° C. over a period of 15minutes under nitrogen. Stirring was continued for 30 minutes at 0° C.,then cooled to −10° C. n-Butyl lithium (1.6 M solution in hexanes, 7.4mL, 11.7 mmol) was added rapidly. Stirring was continued at −10° C. for1 h. Then, anhydrous DMF (5.0 mL) was added, and the mixture was allowedto warm to room temperature over 2 h. The reaction mixture was carefullyquenched with 1N aq. HCl (10 mL). The reaction mixture was diluted withethyl acetate (150 mL). The organic phase was separated, washed withwater (100 mL), then brine (100 mL), and dried over anhydrous Na₂SO₄.The solvent was evaporated to give2-dimethylaminomethyl-1H-indole-5-carbaldehyde as an orange-coloredgummy material. Yield: 0.91 g (crude). This product was used in nextstep without further purification.

To a solution of 2-dimethylaminomethyl-1H-indole-5-carbaldehyde (0.88 gcrude, 4.35 mmol) and 2-amino-4,6-dimethoxy-benzamide (0.85 g, 4.35mmol) in N,N-dimethylacetamide (15 mL) were added sodium hydrogensulfite (58.5 wt %, 0.95 g, 5.22 mmol) and p-toluenesulfonic acid (0.99g, 5.22 mmol). The reaction mixture was stirred at 120° C. for 5 hoursunder nitrogen, then cooled to room temperature, and concentrated underreduced pressure. 30% aqueous sodium carbonate (50 mL) was then added.The separated solid was filtered, washed with water (50 mL), and driedunder vacuum. Crude compound was purified by the Simpliflash system(0-5% methanol in CH₂Cl₂ and 7 N ammonia in methanol 5% in CH₂Cl₂ aseluent) to give the title compound as an off-white solid. Yield: 0.83 g(50%). MP 187-188° C. ¹H NMR (400 MHz, DMSO-d₆): δ 11.82 (s, 1H), 11.34(s, 1H), 8.38 (s, 1H), 7.93 (d, J=8.59 Hz, 1H), 7.40 (d, J=8.59 Hz, 1H),6.73 (s, 1H), 6.49 (s, 1H), 6.40 (s, 1H), 3.90 (s, 3H), 3.85 (s, 3H),3.57 (s, 2H), 2.21 (s, 6H).

Example 60. Preparation ofN-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)methanesulfonamide

A mixture of 4-bromobenzaldehyde (0.250 g, 1.40 mmol),methanesulfonamide (0.154 g, 1.62 mmol), copper iodide (0.0510 g, 0.270mmol), N,N-dimethylglycine (0.0280 g, 0.270 mmol), and potassiumphosphate tribasic (0.716 g, 3.38 mmol) in DMF (5.00 mL) was stirred atreflux for 16 hours. The mixture was diluted with EtOAc (50 mL), washedwith water (50 mL), and then saturated aqueous LiCl (5 mL). The combinedaqueous layers were then back-extracted with EtOAc (50 mL). The organiclayers were combined, washed with brine (50 mL), dried over Na₂SO₄,filtered, and the solvent was removed under reduced pressure, to provideN-(4-formylphenyl)methanesulfonamide (0.161 g, 58%) as a yellow oil.

A mixture of N-(4-formylphenyl)methanesulfonamide (0.161 g, 0.0800mmol), 2-amino-4,6-dimethoxybenzamide (0.159 g, 0.0800 mmol), NaHSO₃(94%, 0.00460 g, 0.0240 mmol), and p-TsOH.H₂O (0.0125 g, 0.120 mmol) inDMA (1.00 mL) was heated at 155° C. for 16 hours. The mixture wasdiluted with EtOAc (50 mL), washed with water (2×50 mL), then brine (50mL), dried over Na₂SO₄, filtered, and the solvent was removed undervacuum. The residue was purified over silica gel (12 g, CH₂Cl₂/MeOH) andthe product was freeze-dried from MeCN/H₂O to provide the title compound(0.0341 g, 11%) as a pale yellow solid. ¹H NMR (300 MHz, DMSO-d₆): δ11.94 (s, 1H), 10.21 (s, 1H), 8.16 (d, J=8.76 Hz, 2H), 7.30 (d, J=8.76Hz, 2H), 6.72 (d, J=2.25 Hz, 1H), 6.52 (d, J=2.25 Hz, 1H), 3.89 (s, 3H),3.85 (s, 3H), 3.09 (s, 3H). MS (ESI) m/z 376 [C₁₇H₁₇N₃O₅S+H]⁺.

Example 61. Preparation of5,7-Dimethoxy-2-(4-(pyridin-4-ylamino)phenyl)quinazolin-4(3H)-one

A mixture of compound2-(4-bromophenyl)-5,7-dimethoxyquinazolin-4(3H)-one) (0.200 g, 0.554mmol), 4-aminopyridine (0.0573 g, 0.609 mmol), Pd₂(dba)₃ (0.0025 g,0.0028 mmol), Xantphos (0.0018 g, 0.0031 mmol), and Cs₂CO₃ (0.253 g,0.776 mmol) in 1,4-dioxane (2.22 mL) under nitrogen was heated at 105°C. for 2 days. The mixture was cooled to room temperature, diluted withEtOAc (200 mL), washed with water (3×75 mL), then brine (75 mL), driedover anhydrous Na₂SO₄, filtered, and the solvent was removed undervacuum. The resulting residue was purified over silica gel (12 g,EtOAc/CHCl₃/MeOH/NH₄OH), to provide the title compound as a white solid.¹H NMR (300 MHz, DMSO-d₆): δ 11.90 (s, 1H), 9.19 (s, 1H), 8.29 (d,J=6.29 Hz, 2H), 8.17 (d, J=8.75 Hz, 2H), 7.30 (d, J=8.75 Hz, 2H), 7.05(d, J=6.29 Hz, 2H), 6.72 (d, J=2.26 Hz, 1H), 6.51 (d, J=2.26 Hz, 1H),3.89 (s, 3H), 3.85 (s, 3H). MS (ESI) m/z 375 [C₂₁H₁₈N₄O₃+H]⁺.

Example 62. Preparation of5,7-Dimethoxy-2-(4-(p-tolylamino)phenyl)quinazolin-4(3H)-one

To a mixture of Pd(OAc)₂ (0.0112 g, 0.0166 mmol) and (S)-(−)-BINAP(0.0155 g, 0.0249 mmol) was added a degassed solution of toluene/t-BuOH(5:1, 3.00 mL) and the mixture was heated at 100° C. for 1 minute. In asecond flask, 2-(4-bromophenyl)-5,7-dimethoxyquinazolin-4(3H)-one)(0.300 g, 0.831 mmol) and degassed toluene/t-BuOH (5:1, 4.00 mL) washeated at 100° C. for 1 minute, t-BuOK (0.130 g, 1.17 mmol) was added,and the mixture heated until most of the solids dissolved. This mixturewas then cooled, additional t-BuOK (0.130 g, 1.17 mmol) was added,followed by p-toluidine (0.107 g, 0.997 mmol), the Pd catalyst/ligandmixture, and additional toluene/t-BuOH (5:1, 3.00 mL). The reaction washeated at 105° C. for 3 days, then cooled to room temperature, dilutedwith water (100 mL), and extracted with EtOAc (2×100 mL). The combinedorganic layers were washed with brine (50 mL), dried over Na₂SO₄,filtered, and the solvent was removed under vacuum. The resultingresidue was purified over silica gel (4 g, CH₂Cl₂/MeOH) and the productwas freeze-dried from MeCN/H₂O to provide the title compound (0.0212 g,6%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆): δ 11.71 (s, 1H), 8.54(s, 1H), 8.06 (d, J=8.82 Hz, 2H), 7.18-6.99 (m, 6H), 6.67 (d, J=2.21 Hz,1H), 6.47 (d, J=2.21 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 2.27 (s, 3H).MS (ESI) m/z 388 [C₂₃H₂₁N₃O₃+H]⁺.

Example 63. Preparation of5,7-Dimethoxy-2-(4-(pyridin-3-ylamino)phenyl)quinazolin-4(3H)-one

A mixture of 2-(4-bromophenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.200g, 0.55 mmol), 3-aminopyridine (0.057 g, 0.61 mmol), Cs₂CO₃ (0.253 g,0.776 mmol), Xantphos (0.002 g, 0.003 mmol), and Pd₂(dba)₃ (0.003 g,0.003 mmol) in dioxane (2 mL) were combined in a microwave tube undernitrogen and irradiated at 300 W, 105° C. for 30 minutes. Then, DMF (1mL) was added and the flask was irradiated for 1 hour at 300 W, 105° C.Then, the mixture was concentrated and purified by silica gelchromatography, eluting with 92:7:1 CHCl₃/MeOH/concentrated NH₄OH. Theresidue was further purified by reverse-phase HPLC, eluting with 10% to90% CH₃CN in H₂O with 0.1% TFA, to afford the title compound (0.105 g,51%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 11.83 (s, 1H), 8.82(s, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.11-8.16 (m, 3H), 7.59-7.62 (m, 1H),7.31-7.35 (m, 1H), 7.13 (d, J=8.7 Hz, 2H), 6.68 (d, J=1.8 Hz, 1H), 6.46(d, J=1.8 Hz, 1H), 3.88 (s, 3H), 3.83 (s, 3H). APCI MS m/z 375 [M+H]⁺.

Example 64. Preparation of4-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)-N,N-dimethylpiperidine-1-carboxamide

To a solution of 4-hydroxypiperidine (5.0 g, 49 mmol) in THF (70 mL) wasadded triethylamine (14.4 mL, 103 mmol) and dimethylcarbamyl chloride(9.0 mL, 98 mmol) slowly. The mixture was stirred at room temperaturefor 1.5 hours. The white precipitate was filtered off, washed with THF.The THF solution was concentrated to dryness then purified with columnchromatography (SiO₂, MeOH/CH₂Cl₂=1:19) to afford4-hydroxypiperidine-1-carboxylic acid dimethylamide as colorless oil.Yield: 7.8 g (94%).

4-Hydroxypiperidine-1-carboxylic acid dimethylamide (1.45 g, 8.40 mmol),4-hydroxbenzenaldehyde (1.02 g, 8.40 mmol) and triphenylphosphine (3.31g, 12.6 mmol) were stirred in THF (6 mL). Diisopropylazodicarboxylate(2.51 mL, 12.6 mmol) was added dropwise to the reaction mixture at roomtemperature over the course of 5 minutes. The mixture was stirred atroom temperature for 21 hours, concentrated, and purified by columnchromatography (SiO₂, hexanes/ethyl acetate=1:1 to neat ethyl acetate),to afford 4-(4-formylphenoxy)-piperidine-1-carboxylic acid dimethylamidea white solid. Yield: 0.7 g (30%).

To a 100 mL round-bottom flask was added 2-amino-4,6-dimethoxybenzamide(196 mg, 1.00 mmol), 4-(4-formylphenoxy)-piperidine-1-carboxylic aciddimethylamide (300 mg, 1.10 mmol), p-toluenesulfonic acid monohydrate(21 mg, 0.10 mmol), sodium hydrogensulfite (216 mg, 1.20 mmol) anddimethylacetamide (5 mL). The mixture was stirred at 115° C. under N₂for 17 hours and cooled to room temperature. Water (20 mL) was added andstirred for 0.5 hours. The precipitate was filtered off, washed withwater, and air dried. The crude product was purified by columnchromatography (SiO₂, neat ethyl acetate, then ethylacetate/methanol=19:1, then CH₂Cl₂/methanol=19:1) to afford the titlecompound as a white solid. Yield: 110 mg (24%). MP 248-249° C. ¹H NMR(400 MHz, DMSO-d₆): δ 11.91 (s, 1H), 8.15 (d, J=8.8 Hz, 2H), 7.10 (d,J=8.8 Hz, 2H), 6.72 (s, 1H), 6.51 (s, 1H), 4.71-4.69 (m, 1H), 3.89 (s,3H), 3.85 (s, 3H), 3.44-3.39 (m, 2H), 3.06-2.99 (m, 2H), 2.74 (s, 6H),2.00-1.96 (m, 2H), 1.64-1.59 (m, 2H).

Example 65. Preparation of2-(4-(1-Acetylpiperidin-4-yloxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

To a solution of 4-hydroxypiperidine (5.00 g, 49.4 mmol) in anhydrousTHF (30 mL) and triethylamine (10 mL, 75 mmol) was added acetyl chloride(3.52 mL, 49.4 mmol). After the addition, the mixture was stirred foranother 2 hours at room temperature. The solid formed was filtered andthe mother liquid was concentrated to yield 5.0 g of crude product,which was purified by column chromatography on silica gel (230-400mesh), using 5% methanol in dichloromethane as eluent, to give1-(4-hydroxy-piperidin-1-yl)-ethanone. Yield: 2.40 g (34%).

To a solution of 1-(4-hydroxy-piperidin-1-yl)-ethanone (1.00 g, 6.90mmol), 4-hydroxybenzaldehyde (0.854 g, 6.90 mmol) and triphenylphosphine(1.83 g, 6.90 mmol) in THF (10 mL) was added dropwise diisopropylazodicarboxylate (DIAD) (1.41 g, 6.90 mmol). The reaction mixture wasstirred at room temperature for 16 hours, THF was evaporated, and theresidue was purified by column chromatography, usingdichloromethane:ethyl acetate:methanol (1:2:0.05) as eluent, to give4-(1-acetyl-piperidin-4-yloxy)-benzaldehyde. Yield: 0.40 g (23%).

To a solution of 2-amino-4, 6-dimethoxy-benzamide (0.20 g, 1.0 mmol) and4-(1-acetyl-piperidin-4-yloxy)-benzaldehyde (0.25 g, 1.0 mmol) inN,N-dimethyl acetamide (5 mL), NaHSO₃ (0.20 g, 1.1 mmol) and p-TSA (20mg, 0.10 mmol) were added and the reaction mixture was heated at 115° C.for 16 hours. The reaction mixture was cooled to room temperature.N,N-dimethylacetamide was removed under reduced pressure. The residuewas diluted with water and the solid was collected; the crude productwas purified by column chromatography on silica gel (230-400 mesh),using 5% methanol in CH₂Cl₂ as eluent, to give the title compound.Yield: 0.2 g (47%). MP 275-277° C. ¹H NMR (400 Hz, CDCl₃): δ 11.94 (s,1H), 8.16 (d, 2H), 7.10 (d, 2H), 6.70 (d, 1H), 6.50 (d, 1H), 4.76 (m,1H), 3.88 (s, 3H), 3.82 (s, 3H), 3.70 (m, 1H), 3.30 (m, 2H), 3.20 (m,1H), 2.04 (s, 3H), 1.95 (m, 2H), 1.64 (m, 1H), 1.52 (m, 1H).

Example 66. Preparation of2-(4-(2-(Isoindolin-2-yl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

To a suspension of2-[4-(2-bromoethoxy)-3,5-dimethylphenyl]-5,7-dimethoxy-3H-quinazolin-4-one(0.50 g, 1.15 mmol) in anhydrous DMF (9 mL) was added isoindoline (0.41mL, 3.46 mmol) and the reaction mixture was stirred at room temperaturefor 16 hours under nitrogen. The solvent was removed under reducedpressure and the residue was triturated with water (50 mL). Theseparated solid was filtered, washed with water and ether, and driedunder vacuum to give the title compound as a white solid. Yield: 0.45 g(83%). MP 202-202.5° C. ¹H NMR (400 MHz, CDCl₃): δ 10.09 (br s, 1H),7.77 (s, 2H), 7.22 (br s, 4H), 6.83 (d, J=2.4 Hz, 1H), 6.46 (d, J=2.4Hz, 1H), 4.11 (s, 4H), 4.03 (t, J=6.0 Hz, 2H), 3.96 (s, 3H), 3.93 (s,3H), 3.22 (t, J=6.0 Hz, 2H), 2.42 (s, 6H).

Example 67. Preparation of2-(3,5-Dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-methoxyquinazolin-4(3H)-one

To a stirred solution of 2-amino-6-methoxy-benzoicacid (3.00 g, 17.9mmol) in THF (90 mL), EDCI (7.89 g, 41.1 mmol) and HOBt (7.95 g, 51.9mmol) were added and stirred at room temperature for 30 minutes thenN-methylmorpholine (6.15 g, 60.0 mmol) and aqueous 50% v/v NH₄OH (12 mL,171.4 mmol) was added. The mixture was stirred for 16 hours at roomtemperature. The solvent was removed under reduced pressure and theresidue was extracted with ethylacetate (4×100 mL), the combined organicphase was washed with water and brine, and dried over anhydrous sodiumsulfate; the solvent was evaporated to give 2-amino-6-methoxy-benzamideas an off-white solid. Yield: 1.90 g, (65%).

To a solution of 2-amino-6-methoxy-benzamide (1.00 g, 6.01 mmol) and4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (1.28 g, 6.59 mmol) inN,N-dimethylacetamide (15 mL) were added NaHSO₃ (58.5 wt %, 0.68 g, 6.50mmol) and p-TSA (0.23 g, 1.20 mmol) and the reaction mixture was heatedat 115° C. for 20 hours, and cooled to room temperature.N,N-dimethylacetamide was removed under reduced pressure. The residuewas diluted with water (50 mL), stirred for 30 minutes, and thenfiltered. The solid was suspended in dichloromethane (30 mL), stirredfor 1 h, filtered, and dried under vacuum to give2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5-methoxy-3H-quinazolin-4-oneas an off-white solid. Yield: 1.1 g (55%).

To a solution of2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5-methoxy3H-quinazolin-4-one(1.10 g, 3.20 mmol) in anhydrous N,N-dimethylformamide (16 mL) wereadded triphenylphosphine (0.92 g, 3.50 mmol) and carbontetrabromide(1.17 g, 3.50 mmol). The reaction mixture was stirred at roomtemperature for 16 hours. DMF was removed under reduced pressure. Theresidue was purified by column chromatography (silica gel 230-400 mesh;3% methanol in dichloromethane as eluent) to give2-[4(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5-methoxy3H-quinazolin-4-oneas an off-white solid. Yield: 0.60 g (46%).

To a solution of2-[4(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5-methoxy3H-quinazolin-4-one(0.50 g, 1.20 mmol) in N,N-dimethylformamide (10 mL) was addedpyrrolidine (0.53 g, 7.40 mmol) and the reaction mixture was stirred atroom temperature for 15 hours. DMF was removed under reduced pressure,the residue was purified by column chromatography (silica gel 230-400mesh; 5% methanol in dichloromethane as eluent) to give the titlecompound as a white solid. Yield: 0.25 g (52%). MP 157-158° C. ¹H NMR(400 MHz, DMSO-d₆): δ 11.95 (s, 1H), 7.89 (s, 2H), 7.70 (t, J=8.19 Hz,1H), 7.24 (d, J=7.8 Hz, 1H), 6.99 (d, J=8.1 Hz, 1H), 3.91-3.89 (m, 2H),3.87 (s, 3H), 2.82 (t, J=6.2 Hz 2H), 2.53-2.50 (m, 4H), 2.30 (s, 6H),1.69 (m, 4H). MS (ES⁺) m/z: 394.61 (M+1).

Example 68. Preparation of5,7-Dichloro-2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-4(3H)-one

To a solution of 2-amino-4,6-dichloro-benzoic acid (4.12 g, 20.0 mmol)in THF (120 mL) were added EDCI (4.22 g, 22.0 mmol), HOBt (2.70 g, 20.0mmol) and N-methylmorpholine (2.22 g, 22.0 mmol). The reaction mixturewas stirred at room temperature for 20 minutes, then 50% (v/v) aqueousNH₄OH solution (2.8 mL, 40.0 mmol) was added. The mixture was stirredfor 20 hours at room temperature. The solvent was evaporated, theresidue was taken in ethyl acetate (200 mL), and water (200 mL) wasadded. The organic phase was separated; the aqueous phase was extractedwith ethyl acetate (200 mL). The combined organic phase was washed withwater (100 mL), then brine (100 mL), and dried over anhydrous sodiumsulfate. The solvent was evaporated and dried under vacuum to give2-amino-4,6-dichloro-benzamide as an off-white solid. Yield: 3.83 g(93%).

To a solution of 2-amino-4,6-dichloro-benzamide (1.54 g, 7.50 mmol) and4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (1.46 g, 7.50 mmol) inN,N-dimethylacetamide (15 mL) were added sodium hydrogen sulfite (58.5wt %, 1.51 g, 8.25 mmol) and p-toluenesulfonicacid monohydrate (0.28 g,1.50 mmol). The reaction mixture was stirred at 120° C. for 16 hoursunder nitrogen, and then cooled to room temperature. Solvent wasevaporated under reduced pressure. Water (100 mL) was added. Theseparated solid was filtered, washed with water (50 mL), and dried undervacuum. Crude compound was further washed with ether and dried undervacuum to give5,7-dichloro-2-[4-(2-hydroxy-ethoxy)-3,5-dimethylphenyl]-3H-quinazolin-4-oneas a white solid. Yield: 2.42 g (85%).

To a solution of5,7-dichloro-2-[4-(2-hydroxy-ethoxy)-3,5-dimethylphenyl]-3H-quinazolin-4-one(1.14 g, 3.00 mmol) in anhydrous DMF (15 mL) was added carbontetrabromide (1.10 g, 3.30 mmol). Then, triphenylphosphine (0.86 g, 3.30mmol) was added in small portions. The reaction mixture was stirred atroom temperature for 16 hours under nitrogen. Solvent was evaporatedunder reduced pressure. The residue was washed with ethyl acetate (50mL) and dried under vacuum to give2-[4-(2-bromo-ethoxy)-3,5-dimethylphenyl]-5,7-dichloro-3H-quinazolin-4-oneas a white solid. Yield: 0.46 g (35%).

To a solution of2-[4-(2-bromo-ethoxy)-3,5-dimethylphenyl]-5,7-dichloro-3H-quinazolin-4-one(0.44 g, 1.00 mmol) in anhydrous DMF (10 mL) was added pyrrolidine (0.28g, 4.00 mmol). The reaction mixture was stirred at room temperature for6 hours under nitrogen. Solvent was evaporated under reduced pressure.Water (50 mL) was added. The separated solid was filtered, washed withwater (20 mL), and dried under vacuum. The crude compound was purifiedby the Simpliflash system (0-5% methanol in CH₂Cl₂ and 5% methanol(containing 7.0 M ammonia) in CH₂Cl₂ as eluent) to give the titlecompound as a white solid. Yield: 0.31 g (72%). MP 209-210° C. ¹H NMR(400 MHz, DMSO-d₆): δ 12.39 (br s, 1H), 7.90 (s, 2H), 7.71 (d, J=1.95Hz, 1H), 7.60 (d, J=1.95 Hz, 1H), 3.91 (t, J=5.85 Hz, 2H), 2.83 (t,J=6.05 Hz, 2H), 2.55 (m, 4H), 2.31 (s, 6H), 2.01 (m, 4H). MS (ES+) m/z432.54 (100%), 434.49 (90%).

Example 69. Preparation of2-(3,5-Dimethyl-4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-5,7-dimethoxy-3-(3-(pyrrolidin-1-yl)propyl)quinazolin-4(3H)-one

To a solution of2-(4-hydroxy-3,5-dimethyl-phenyl)-5,7-dimethoxy-3H-quinazolin-4-one(0.70 g, 2.14 mmol) in anhydrous THF (50 mL) were added triphenylphosphine (1.69 g, 6.43 mmol), 3-bromo-1-propanol (0.60 g, 4.34 mmol)and N,N-diisopropylethyl amine (0.42 g, 3.22 mmol). To this stirredsolution was added diethyl azodicarboxylate (1.13 g, 6.43 mmol). Thereaction mixture was stirred at room temperature for 48 hours undernitrogen. Ethyl acetate (400 mL) was added; the organic phase wasseparated, washed with water (100 mL), then brine (100 mL), and driedover anhydrous Na₂SO₄. Solvent was removed under reduced pressure. Thecrude material was purified by the Simpliflash system (5:95 ethylacetate:hexane as eluent) to give2-[4-(3-bromo-propoxy)-3,5-dimethyl-phenyl]-3-(3-bromo-propyl)-5,7-dimethoxy-3H-quinazolin-4-oneas a white solid. Yield: 0.765 g (63%).

To a solution of2-[4-(3-bromo-propoxy)-3,5-dimethyl-phenyl]-3-(3-bromo-propyl)-5,7-dimethoxy-3H-quinazolin-4-one(0.76 g, 1.35 mmol) in DMF (10 mL) were added pyrrolidine (0.77 g, 10.77mmol). The reaction mixture was stirred at room temperature for 16hours. Then, water was added and product was extracted with ethylacetate (2×200 mL). The combined organic layer was washed with water,then brine, and dried over Na₂SO₄. Solvent was evaporated to give thetitle compound as a white solid. Yield: 0.12 g (16%). MP 109-111° C. ¹HNMR (400 MHz, CDCl₃): δ 8.16 (s, 2H), 6.93 (d, J=2.4 Hz, 1H), 6.44 (d,J=2.4 Hz, 1H), 4.71 (t, J=6.4 Hz, 2H), 3.94 (s, 3H), 3.93 (s, 3H), 3.87(t, J=6.0 Hz, 2H), 2.75 (m, 4H), 2.60 (m, 8H), 2.37 (s, 6H), 2.16 (m,2H), 2.05 (m, 2H), 1.82 (m, 8H). MS (ES) m/z: 549.75 (M+1). Analysiscalculated for C₃₂H₄₄N₄O₄.0.5H₂O (FW 557.73), %: C, 68.91; H, 8.13; N,10.05. Found, %: C, 68.71; H, 8.56; N, 9.74.

Example 70. Preparation of2-(4-(2-(4-Acetylpiperazin-1-yl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

To a suspension of2-[4-(2-bromoethoxy)-3,5-dimethylphenyl]-5,7-dimethoxy-3H-quinazolin-4-one(0.35 g, 0.81 mmol) in anhydrous DMF (9 mL) was added 1-acetylpyperazine(0.31 g, 2.42 mmol) and the reaction mixture was stirred at roomtemperature under nitrogen for 32 hours. Solvent was removed underreduced pressure and water (50 mL) was added. The separated solid wasfiltered, washed with water and ether, and dried under vacuum, to givethe title compound as a white solid. Yield: 0.28 g (72%). MP 213-214° C.¹H NMR (400 MHz, CDCl₃): δ 9.87 (br s, 1H), 7.74 (s, 2H), 6.83 (d, J=2.4Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 3.97 (s, 3H), 3.95 (t, J=6.0 Hz, 2H),3.93 (s, 3H), 3.69 (t, J=5.0 Hz, 2H), 3.53 (t, J=5.0 Hz, 2H), 2.84 (t,J=5.6 Hz, 2H), 2.62 (t, J=5.0 Hz, 2H), 2.57 (t, J=5.0 Hz, 2H), 2.39 (s,6H), 2.11 (s, 3H). MS (ES⁻) m/z 479.65 (100%, M−1).

Example 71. Preparation of2-(4-(2-(1H-Imidazol-1-yl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

To a solution of2-[4-(2-bromoethoxy)-3,5-dimethylphenyl]-5,7-dimethoxy-3H-quinazolin-4-one(0.12 g, 0.27 mmol) in acetone (5 mL) was added imidazole (0.18 g, 2.70mmol) and Cs₂CO₃ (0.26 g, 0.80 mmol). The reaction mixture was stirredat room temperature for 16 hours. Solvent was removed under reducedpressure, and the residue was purified by column chromatography (silicagel 230-400 mesh; 3% methanol in dichloromethane as eluent) to give thetitle compound as a white solid. Yield: 0.04 g (35%). MP 218-219° C. ¹HNMR (400 MHz, DMSO-d₆): δ 11.80 (br s, 1H), 7.83 (s, 2H), 7.72 (s, 1H),7.29 (s, 1H), 6.92 (s, 1H), 6.70 (d, J=2.4 Hz, 1H), 6.49 (d, J=2.4 Hz,1H), 4.36 (t, J=4.8 Hz, 2H), 4.02 (t, J=4.8 Hz, 2H), 3.86 (s, 3H), 3.81(s, 3H), 2.06 (s, 6H). MS (ES) m/z: 419.57 (M−1).

Example 72. Preparation of2-(3,5-Dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-7-methoxyquinazolin-4(3H)-one

To a stirred solution of 2-amino-4-methoxy-benzoic acid (3.00 g, 17.9mmol) in THF (90 mL), EDCI (7.89 g, 41.1 mmol) and HOBt (7.95 g, 51.9mmol) were added and stirred at room temperature for 30 minutes. Then,N-methylmorpholine (6.15 g, 60.0 mmol) and aqueous 50% (v/v) NH₄OH (12mL, 171.4 mmol) were added. The mixture was stirred for 16 hours at roomtemperature. The solvent was removed under reduced pressure and theresidue was extracted with ethyl acetate (4×100 mL). The combinedorganic phase was washed with water, then brine, and dried overanhydrous sodium sulfate. Solvent was evaporated to give2-amino-4-methoxy-benzamide as an off-white solid. Yield: 1.80 g, (60%).

To a solution of 2-amino-4-methoxy-benzamide (1.00 g, 6.01 mmol) and4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (1.28 g, 6.59 mmol) inN,N-dimethylacetamide (15 mL) were added NaHSO₃ (58.5 wt %, 0.68 g, 6.50mmol) and p-TSA (0.23 g, 1.20 mmol) and the reaction mixture was stirredat 115° C. for 16 hours, and cooled to room temperature. Solvent wasremoved under reduced pressure. The residue was diluted with water (50mL), stirred for 30 minutes, and then filtered. The solid was suspendedin dichloromethane (30 mL), stirred for 1 hour, filtered, and driedunder vacuum, to give2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-7-methoxy-3H-quinazolin-4-oneas an off-white solid. Yield: 1.20 g (58%).

To a solution of2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-7-methoxy-3H-quinazolin-4-one(1.20 g, 3.52 mmol) in anhydrous DMF (15 mL) were addedtriphenylphosphine (1.00 g, 3.80 mmol) and carbontetrabromide (1.27 g,3.80 mmol). The reaction mixture was stirred at room temperature for 16hours. DMF was removed under reduced pressure. The residue was purifiedby column chromatography (silica gel 230-400 mesh; 3% methanol indichloromethane as eluent) to give2-[4(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-7-methoxy3H-quinazolin-4-oneas an off-white solid. Yield: 0.37 g (26%).

To a solution of2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-7-methoxy-3H-quinazolin-4-one(0.30 g, 0.74 mmol) in DMF (5 mL) was added pyrrolidine (0.31 g, 4.36mmol) and the reaction mixture was stirred at room temperature for 15hours. DMF was removed under reduced pressure, and the residue waspurified by column chromatography (silica gel 230-400 mesh; 5% methanolin dichloromethane as eluent) to give the title compound as a whitesolid. Yield: 0.13 g (44%). MP 218-220° C. ¹H NMR (400 MHz, DMSO-d₆): δ12.13 (br s, 1H), 8.03 (d, J=8.98 Hz, 1H), 7.90 (s, 2H), 7.16 (d, J=2.3Hz, 1H), 7.07 (dd, J=8.9 and 2.7 Hz, 1H), 3.92-3.89 (m, 5H), 2.83 (t,J=5.8 Hz, 2H), 2.54-2.50 (m, 4H), 2.31 (s, 6H), 1.73 (m, 4H). MS (ES⁺)m/z: 394.62 (M+1).

Example 73. Preparation of2-(3,5-Dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

To a solution of2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one(0.17 g, 0.39 mmol) in N,N-dimethylformamide (0.5 mL) was addedN-methylpiperazine (0.44 mL, 3.92 mmol) and the reaction mixture wasstirred at room temperature for 15 hours. N,N-dimethylformamide wasremoved under reduced pressure. The residue was purified by columnchromatography (silica gel 230-400 mesh; 5% methanol in dichloromethaneas eluent) to give the title compound as a white solid. Yield: 60 mg(33.8%). MP 180-182° C. ¹H NMR (400 MHz, DMSO-d₆): δ 11.76 (s, 1H), 7.89(s, 2H), 6.73 (d, J=2.4 Hz, 1H), 6.51 (d, J=2.4 Hz, 1H), 3.88 (m, 5H),3.84 (s, 3H), 2.68 (t, J=5.6 Hz, 2H), 2.50 (br s, 4H), 2.32 (br s, 4H),2.30 (s, 6H), 2.15 (s, 3H). MS (ES⁺) m/z: 453.21 (M+1).

Example 74. Preparation of2-(3,5-Dimethyl-4-(2-(piperidin-1-yl)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

To a solution of2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one(0.34 g, 0.78 mmol) in DMF (10 mL) was added piperidine (0.27 g, 3.14mmol). The reaction mixture was stirred at room temperature for 16hours. Then, water was added and the product was extracted with ethylacetate (2×200 mL). The combined organic layer was washed with water,then brine, and dried over anhydrous Na₂SO₄. Solvent was evaporated togive the title compound as a white solid. Yield: 0.33 g (96%). ¹H NMR(400 MHz, DMSO-d₆): δ 11.80 (br s, 1H), 7.87 (s, 2H), 6.72 (d, J=2.4 Hz,1H), 6.49 (d, J=2.0 Hz, 1H), 3.86 (m, 6H), 3.82 (s, 2H), 2.63 (t, J=5.6Hz, 2H), 2.42 (m, 4H), 2.28 (s, 6H), 1.50 (m, 4H), 1.37 (m, 2H). MS (ES)m/z 438.63 (M+1).

Example 75. Preparation of5,7-Dimethoxy-2-(3-methyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-4(3H)-one

To a solution of 4-hydroxy-3-methylbenzaldehyde (1.10 g, 8.08 mmol) inanhydrous DMF (12 mL) was added K₂CO₃ (2.23 g, 16.16 mmol) and ethylenecarbonate (1.42 g, 16.16 mmol) at room temperature. The resultingreddish-orange suspension was stirred at 110° C. for 6 hours undernitrogen. DMF was removed and the residue was diluted with water (50 mL)and dichloromethane (50 mL). The organic phase was separated, and theaqueous phase was extracted with dichloromethane (2×20 mL). The combinedorganic phase was washed with brine and dried over anhydrous magnesiumsulfate. The solvent was removed under reduced pressure to obtain4-(2-hydroxy-ethoxy)-3-methylbenzaldehyde as a brown oil. Yield: 1.46 g(100%).

To a solution of 4-(2-hydroxy-ethoxy)-3-methylbenzaldehyde (1.46 g, 8.08mmol) and 2-amino-4,6-dimethoxybenzamide (1.58 g, 8.08 mmol) inN,N-dimethylacetamide (20 mL) were added NaHSO₃ (58.5 wt %, 2.20 g,12.12 mmol) and p-toluenesulfonic acid monohydrate (0.38 g, 2.02 mmol).The reaction mixture was stirred at 110° C. for 16 hours, then cooled toroom temperature. N,N-dimethylacetamide was removed under reducedpressure. The residue was triturated with water (50 mL). The resultingslurry was filtered and solid was washed with water, ether, and hexanesto obtain2-[4-(2-hydroxy-ethoxy)-3-methyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-oneas a beige solid. Yield: 2.75 g (95%).

Tetrabromomethane (3.26 g, 9.82 mmol) was added to a solution oftriphenylphosphine (2.58 g, 9.82 mmol) in anhydrous DMF (20 mL) at 0° C.A solution of2-[4-(2-hydroxy-ethoxy)-3-methyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one(1.75 g, 4.91 mmol) in DMF (7 mL) was then added dropwise and stirredthe reaction mixture at room temperature for 16 hours. The solvent wasremoved under reduced pressure and the residue was diluted with water(50 mL) and extracted with dichloromethane (4×25 mL). The combinedorganic phase was washed with brine and dried over anhydrous magnesiumsulfate. The solvent was removed and the solid was triturated withether. The resulting slurry was filtered and washed with ether severaltimes (to remove the triphenylphosphine oxide) and finally with asolution of dichloromethane-ether (1:1) to obtain2-[4-(2-bromo-ethoxy)-3-methyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-oneas an off-white solid. Yield: 0.70 g (34%).

To a suspension of2-[4-(2-bromo-ethoxy)-3-methyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one(0.70 g, 1.67 mmol) in anhydrous DMF (9 mL) was added pyrrolidine (0.55mL, 6.68 mmol) and the reaction mixture was stirred at room temperatureunder nitrogen for 20 hours. Solvent was removed under reduced pressureand the residue was purified by column chromatography (silica gel230-400 mesh; 9% methanol in dichloromethane as eluent) to give thetitle compound as an off-white solid. Yield: 0.62 g (90.6%). MP 230-231°C. ¹H NMR (400 MHz, CDCl₃): δ 9.96 (br s, 1H), 7.91-7.89 (m, 2H), 6.93(d, J=7.6 Hz, 1H), 6.82 (d, J=2.4 Hz, 1H), 6.44 (d, J=2.4 Hz, 1H), 4.21(t, J=6.0 Hz, 2H), 3.98 (s, 3H), 3.93 (s, 3H), 2.98 (t, J=6.0 Hz, 2H),2.69 (br s, 4H), 2.32 (s, 3H), 1.84-1.81 (m, 4H). MS (ES⁻) m/z 408.13(M−1, 100%), MS (ES⁺) m/z 410.14 (M+1, 75%).

Example 76. Preparation of3-(2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-1-isopropylimidazolidine-2,4-dione

To a mixture of urea (5.00 g, 83.0 mmol) in anhydrous toluene (13 mL)was added chloroacetyl chloride (6.6 mL, 83.0 mmol) and the reactionmixture was heated to reflux for 2 hours. The reaction mixture wascooled to room temperature and toluene was removed by filtration. Theresulting solid was further washed with toluene (10 mL) and mixed withwater (100 mL). The solid was filtrated and washed with cold water (50mL) and dried to give (2-chloroacetyl)-urea as a white solid. Yield:10.3 g (91%).

(2-Chloroacetyl)-urea (0.68 g, 5.00 mmol) and isopropylamine (0.86 mL,10.0 mmol) in DMF (10 mL) was stirred for 6 h at room temperature andthen heated to 135° C. for 4 hours. DMF was removed under vacuum and theresidue was purified by column chromatography (silica gel 230-400 mesh;eluting with hexane:dichloromethane:ethyl acetate 2.5:1.0:0.5) to give1-isopropyl-imidazolidine-2,4-dione as a white solid. Yield: 0.20 g(28%).

To a solution of 1-isopropyl-imidazolidine-2,4-dione (0.10 g, 0.70 mmol)in N,N-dimethylformamide (5 mL) was added sodium hydride (60% in mineraloil, 31 mg, 0.77 mmol) and the reaction mixture was stirred for 10minutes. Then,2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one(0.32 g, 0.73 mmol) was added. The reaction mixture was stirred at 55°C. for 16 hours, then poured into water (100 mL). The solid was filteredand dried. The crude compound was purified by column chromatography(silica gel 230-400 mesh; eluting with 2:1 ethyl acetate anddichloromethane) to give the title compound as a white solid. Yield:0.09 g (26.0%). MP 219-221° C. ¹H NMR (400 MHz, DMSO): δ 9.64 (s, 1H),7.69 (s, 2H), 6.82 (d, J=2.4 Hz, 1H), 6.45 (d, J=2.4 Hz, 1H), 4.42 (m,1H), 4.02 (m, 2H), 3.98 (m, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 3.85 (s,2H), 2.32 (s, 6H) 1.22 (d, J=6.4 Hz, 6H). MS (ES⁺) m/z: 495.16 (M+1).

Example 77. Preparation of2-(3,5-Dimethyl-4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

To a solution of 4-hydroxy-3, 5-dimethyl benzaldehyde (5.0 g, 33.29mmol) in DMF (30 mL) were added 3-bromo propan-1-ol (5.56 g, 39.95 mmol)and Cs₂CO₃ (16.24 g, 50.0 mmol). Then, the reaction mixture was stirredat room temperature for 48 hours. Then, water was added and the productswere extracted with ethyl acetate (2×250 mL). The combined organic phasewas washed with water (100 mL), then brine (100 mL), and dried overanhydrous Na₂SO₄. Removal of solvent gave4-(3-hydroxypropoxy)-3,5-dimethyl benzaldehyde as a colorless liquid.Yield: 5.38 g (77%).

To a solution of 2-amino-4, 6-dimethoxy-benzamide (1.3 g, 6.63 mmol) and4-(3-hydroxypropoxy)-3,5-dimethyl benzaldehyde (1.38 g, 6.63 mmol) inN,N-dimethyl acetamide (10 mL), NaHSO₃ (1.30 g, 7.3 mmol), and p-TSA(252 mg, 1.32 mmol) were added and the reaction mixture was heated at115° C. for 26 hours, then cooled to room temperature. The solvent wasremoved under reduced pressure. Then, water (100 mL) was added andstirred for 1 hour at room temperature. The separated solids werefiltered and dried. The solids were again washed with diethyl ether togive crude product2-[4-(3-hydroxy-propoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-oneas an off-white solid. Yield: 1.69 g (66%).

To a solution of2-[4-(3-hydroxy-propoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one(1.39 g, 3.62 mmol) in DMF (15 mL) were added PPh₃ (1.04 g, 3.98 mmol)and CBr₄ (1.32 g, 3.98 mmol). The reaction mixture was stirred at roomtemperature for 16 hours. Then, solvent was removed under reducedpressure. The residue was triturated with ether and ethyl acetate. Thesolids were dried and purified by the Simpliflash system, using 2%methanol in CH₂Cl₂, to give2-[4-(3-bromo-propoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-oneas a white solid. Yield: 940 mg (58%).

To a solution of 2-[4-(3-bromo-propoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (340 mg, 0.76 mmol)in DMF (10 mL) was added pyrrolidine (433 mg, 6.08 mmol). Then, thereaction mixture was stirred at room temperature for 16 hours. Then,water was added and the solids were filtered. The solids were washedwith water and dried to give the title compound as a white solid. Yield:307 mg (92%). ¹H NMR (400 MHz, DMSO-d₆): δ 11.80 (s, 1H), 7.87 (s, 2H),6.71 (d, J=2.0 Hz, 1H), 6.49 (d, J=2.0 Hz, 1H), 3.86 (s, 3H), 3.82 (m,5H), 2.59 (t, J=6.8 Hz, 2H), 2.42 (m, 4H), 2.26 (s, 6H), 1.89 (m, 2H),1.67 (m, 4H). MS (ES) m/z: 438.16 (M+1).

Example 78. Preparation of5,7-Dimethoxy-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-4(3H)-one

Carbon tetrabromide (0.26 g, 0.77 mmol) was added to a solution oftriphenylphosphine (0.24 g, 0.92 mmol) in anhydrous DMF (5 mL) at 0° C.A solution of2-[4-(2-hydroxy-ethoxy)-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.21g, 0.61 mmol) in DMF (2 mL) was then added dropwise and stirred at roomtemperature for 16 hours. Solvent was removed under reduced pressure andthe residue was diluted with water (10 mL) and extracted withdichloromethane (4×10 mL). The combined organic phase was washed withbrine and dried over anhydrous magnesium sulfate. Solvent was removedand the residual solid was triturated with ether. The resulting slurrywas filtered and washed with ether several times (to remove thetriphenylphosphine oxide) and finally with a solution ofdichloromethane-ether (1:4) to obtain2-[4-(2-bromo-ethoxy)-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one as anoff-white solid. Yield: 0.25 g (quantitative).

To a suspension of2-[4-(2-bromo-ethoxy)-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.25 g,0.61 mmol) in anhydrous DMF (10 mL) was added pyrrolidine (0.20 mL, 2.45mmol) and the reaction mixture was stirred at room temperature undernitrogen for about 20 hours. Solvent was removed under reduced pressureand the residual solid was triturated with water. The resulting slurrywas filtered and washed with ether and hexanes. The crude product waspurified by column chromatography (silica gel 230-400 mesh; 10% methanolin dichloromethane as eluent) to give the title compound as a whitesolid. Yield: 0.11 g (44%). MP 226-227° C. ¹H NMR (400 MHz, CDCl₃): δ10.08 (br s, 1H), 8.07 (d, J=8.4 Hz, 2H), 7.06 (d, J=8.8 Hz, 2H), 6.81(d, J=1.95 Hz, 1H), 6.45 (d, J=1.95 Hz, 1H), 4.21 (t, J=5.6 Hz, 2H),3.99 (s, 3H), 3.93 (s, 3H), 2.97 (t, J=5.6 Hz, 2H), 2.68 (br s, 4H),1.84 (br s, 4H). MS (ES⁺): m/z 198.65 (100%), 396.10 (M+1, 70%).

Example 79. Preparation of2-(3,5-Dimethyl-4-(3-(pyrrolidin-1-yl)propyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

To a solution of 2-amino-4,6-dimethoxy-benzamide (0.80 g, 4.00 mmol) and4-(3-hydroxy-propyl)-3,5-dimethyl-benzaldehyde (0.98 g, 5.1 mmol) inN,N-dimethylacetamide (15 mL) were added NaHSO₃ (58.5 wt %, 0.80 g, 4.40mmol) and p-TSA (0.155 g, 0.81 mmol) and the reaction mixture was heatedat 115° C. for 16 hours, then cooled to room temperature.N,N-dimethylacetamide was removed under reduced pressure. The residuewas diluted with water (50 mL), stirred for 30 minutes, and thenfiltered and washed with water. The crude compound was purified bycolumn chromatography (silica gel 230-400 mesh; 5% methanol indichloromethane as eluent) to give2-[4-(3-hydroxy-propyl)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-oneas an off-white solid. Yield: 1.10 g (73%).

To a solution of2-[4-(3-hydroxy-propyl)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one(1.00 g, 2.70 mmol) in anhydrous N,N-dimethylformamide (15 mL) wereadded triphenylphosphine (0.78 g, 3.00 mmol) and carbon tetrabromide(1.00 g, 3.00 mmol). The reaction mixture was stirred at roomtemperature for 16 hours. DMF was removed under reduced pressure. Theresidue was purified by column chromatography (silica gel 230-400 mesh;3% methanol in dichloromethane as eluent) to give2-[4-(3-bromo-propyl)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-oneas an off-white solid. Yield: 0.60 g (51%).

To a solution of2-[4-(3-bromo-propyl)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one(0.40 g, 0.92 mmol) in N,N-dimethylformamide (10 mL) was addedpyrrolidine (0.39 g, 5.52 mmol) and the reaction mixture was stirred atroom temperature for 16 hours. DMF was removed under reduced pressure,the residue was purified by column chromatography (silica gel 230-400mesh; 5% methanol ammonia in dichloromethane as eluent) to give thetitle compound as a white solid. Yield: 0.27 g (69%). MP 194-196° C. ¹HNMR (400 MHz, DMSO-d₃): δ 11.79 (br s, 1H), 7.81 (s, 2H), 6.72 (d, J=2.3Hz, 1H), 6.50 (d, J=2.3 Hz, 1H), 4.00 (s, 3H), 3.87 (s, 3H), 2.67-2.63(m, 2H), 2.49-2.46 (m, 6H), 2.33 (s, 6H), 1.70-1.67 (m, 4H), 1.59-1.53(m, 2H). MS (ES⁺) m/z: 422.17 (M+1).

Example 80. Preparation of2-(3,5-Dimethyl-4-(4-(pyrrolidin-1-yl)butoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

To a solution of 4-hydroxy-3,5-dimethyl benzaldehyde (5.00 g, 33.3 mmol)in DMF (30 mL) were added 4-bromo-butan-1-ol (6.11 g, 39.9 mmol) andCs₂CO₃ (16.2 g, 50.0 mmol). The reaction mixture was stirred at roomtemperature for 48 hours, then water (100 mL) was added, and theproducts were extracted with ethyl acetate (2×200 mL). The combinedorganic phase was washed with water (100 mL), then brine (100 mL), anddried over anhydrous Na₂SO₄. Solvent was removed and the crude productwas purified by the Simpliflash system, using 40% ethyl acetate inhexane as eluent, to give 4-(4-hydroxybutoxy)-3,5-dimethyl benzaldehydeas a colorless liquid. Yield: 0.66 g (7%).

To a solution of 2-amino-4,6-dimethoxy-benzamide (497 mg, 2.53 mmol) and4-(4-hydroxybutoxy)-3,5-dimethyl benzaldehyde (660 mg, 2.53 mmol) inN,N-dimethyl acetamide (10 mL), NaHSO₃ (58.5 wt %, 496 mg, 2.79 mmol)and p-TSA (96 mg, 0.50 mmol) were added and the reaction mixture washeated at 115° C. for 16 hours and then cooled to room temperature. Thesolvent was removed under reduced pressure. Water (100 mL) was added andstirred for 1 hour at room temperature. The solid separated was filteredand dried. The solid was further washed with diethyl ether to giveproduct2-[4-(4-hydroxy-butoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-oneas a white solid. Yield: 1.69 g (82%).

To a solution of2-[4-(4-hydroxy-butoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one(675 mg, 1.69 mmol) in DMF (10 mL) were added PPh₃ (489 mg, 1.86 mmol)and CBr₄ (619 mg, 1.86 mmol). The reaction mixture was stirred at roomtemperature for 16 hours. Solvent was removed under reduced pressure.The residue was triturated with ether and ethyl acetate. The solid wasdried and then purified by the Simpliflash system using 5% methanol inCH₂Cl₂ as the eluent to give2-[4-(4-bromo-butoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-oneas a white solid. Yield: 494 mg (63%).

To a solution of2-[4-(4-bromo-butoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one(494 mg, 1.07 mmol) in DMF (10 mL) was added pyrrolidine (609 mg, 8.57mmol). The reaction mixture was stirred at room temperature for 16hours. Water (100 mL) was added and the product was extracted with ethylacetate (2×200 mL). The combined organic phase was washed with water,then brine, and dried over anhydrous Na₂SO₄. Solvent was evaporated togive the title compound as a white solid. Yield: 278 mg (57%). MP180-181° C. ¹H NMR (400 MHz, CDCl₃): δ 7.68 (s, 2H), 6.83 (d, J=2.4 Hz,1H), 6.46 (d, J=2.4 Hz, 1H), 3.97 (s, 3H), 3.92 (s, 3H), 3.83 (t, J=6.4Hz, 2H), 2.56 (m, 6H), 2.36 (s, 6H), 1.88 (m, 2H), 1.79 (m, 6H). MS (ES)m/z: 452.21 (M+1).

Example 81. Preparation of2-(3,5-Dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-8-methoxyquinazolin-4(3H)-one

To a solution of 2-amino-3-methoxy benzoic acid (5.00 g, 29.9 mmol) inTHF (50 mL) were added EDCI (6.88 g, 35.9 mmol), HOBt (4.85 g, 35.9mmol), N-methylmorpholine (3.60 g, 35.9 mmol), and aqueous ammonia (50%v/v, 30 mL). Then, the reaction mixture was stirred at room temperaturefor 48 hours. Then, water was added and the product was extracted withethyl acetate (2×250 mL). The combined organic phase was washed withwater, then brine, and dried over anhydrous Na₂SO₄. Removal of solventgave product 2-amino-3-methoxy-benzamide as a light orange solid. Yield:1.70 g (34%).

To a solution of 2-amino-3-methoxy-benzamide (700 mg, 4.22 mmol) and4-(2-hydroxyethoxy)-3,5-dimethyl benzaldehyde (823 mg, 4.22 mmol) inN,N-dimethyl acetamide (10 mL) were added NaHSO₃ (58.5 wt %, 841 mg,4.64 mmol) and p-TSA (160 mg, 0.84 mmol). The reaction mixture washeated at 115° C. for 16 hours, then cooled to room temperature. Solventwas removed under reduced pressure. Water (100 mL) was added and stirredfor 1 hour at room temperature. The solid separated was filtered anddried. The solid was further washed with diethyl ether to give crudeproduct2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-8-methoxy-3H-quinazolin-4-oneas an off-white solid. Yield: 1.2 g (84%).

To a solution of2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-8-methoxy-3H-quinazolin-4-one(1.20 g, 3.53 mmol) in DMF (10 mL) were added PPh₃ (1.02 g, 3.88 mmol)and CBr₄ (1.29 g, 3.88 mmol). The reaction mixture was stirred at roomtemperature for 16 hours. Solvent was removed under reduced pressure.The residue was triturated with ether and ethyl acetate. The solid wasdried under vacuum and purified by the Simpliflash system, using 2%methanol in CH₂Cl₂ as eluent, to give2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-8-methoxy-3H-quinazolin-4-oneas a white solid. Yield: 0.547 g (38%).

To a solution of2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-8-methoxy-3H-quinazolin-4-one(537 mg, 1.33 mmol) in DMF (10 mL) was added a pyrrolidine (758 mg,10.66 mmol). The reaction mixture was stirred at room temperature for 16hours. Water (100 mL) was added and the solid separated was filtered anddried under vacuum. The solid was triturated with ether and dried togive the title compound as a white solid. Yield: 232 mg (44%). MP231-232° C. ¹H NMR (400 MHz, CDCl₃): δ 10.30 (s, 1H), 7.90 (dd, J=8.0Hz, 1H), 7.806 (br s, 2H), 7.42 (t, J=8.4 Hz, 1H), 7.24 (d, J=8.4 Hz,1H), 4.04 (s, 3H), 3.95 (t, J=6.4 Hz, 2H), 2.93 (t, J=6.0 Hz, 2H), 2.65(m, 4H), 2.40 (s, 6H), 1.84 (m, 4H). MS (ES) m/z: 394.15 (M+1).

Example 82. Preparation of3-(2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-5-phenylimidazolidine-2,4-dione

To a suspension of2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one(0.50 g, 1.35 mmol) in THF (20 mL), were added5-phenyl-imidazolidine-2,4-dione (0.24 g, 1.35 mmol) and triphenylphosphine (0.35 g, 1.35 mmol), then diethyl azodicarboxylate (0.43 mL,2.70 mmol) was added and the reaction mixture was stirred at roomtemperature for 16 hours. Solvent was evaporated in vacuo and theresidue was washed with dichloromethane and ether. The residue wasdissolved in acetic acid and purified by preparative HPLC. The compoundwas further washed with dichloromethane and ether (1:1, 20 mL) to obtainthe title compound as a white solid. Yield: 0.07 g (10%). MP219.6-221.4° C. ¹H NMR (400 MHz, DMSO-d₆): δ 8.81 (s, 1H), 7.86 (s, 2H),7.37 (m, 5H), 6.71 (s, 1H), 6.48 (s, 1H), 3.94 (m, 4H), 3.86 (s, 3H),3.82 (s, 3H), 2.18 (s, 6H). MS (ES) m/z: 529.29 (M⁺+1).

Example 83. Preparation of3-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)benzyl)imidazolidine-2,4-dione

Hydantoin (0.80 g, 8.00 mmol) was dissolved in DMF (10 mL) and cooled to0° C. Sodium hydride (60% in mineral oil, 88 mg, 2.20 mmol) was added.The mixture was stirred at room temperature for 3 hours.4-(Bromomethyl)benzaldehyde (0.40 g, 2.00 mmol) was added. The mixturewas stirred at room temperature for 2.5 days. Saturated aqueous NH₄Cl (1mL) was added. The mixture was concentrated to dryness. Water (10 mL)was added, extracted with dichloromethane, and the organic phase wasdried over anhydrous Na₂SO₄. Solvent was removed and the crude compoundwas purified by column chromatography (silica gel 230-400 mesh; 5%methanol in CH₂Cl₂ as eluent) to give4-(2,5-dioxo-imidazolidin-1-ylmethyl)-benzaldehyde as a white solid.Yield: 0.28 g (64%).

To a solution of 2-amino-4,6-dimethoxy-benzamide (0.19 g, 0.98 mmol) inN,N-dimethylacetamide (4 mL) were added4-(2,5-dioxo-imidazolidin-1-ylmethyl)-benzaldehyde (0.19 g, 0.89 mmol),sodium hydrogen sulfite (58.5 wt %, 0.24 g, 1.30 mmol) andp-toluenesulfonic acid monohydrate (34 mg, 0.18 mmol) and the reactionmixture was stirred at 115° C. for 17 hours under nitrogen, then cooledto room temperature. The precipitate was filtered, washed with methanol,water, then methanol, and dried in air. The solid was suspended in hotDMSO (approximately 3 mL); saturated aqueous NaHCO₃ (approximately 3 mL)and water were added. The solid was filtered, washed with water, thenmethanol, and air dried to give the title compound as a light yellowsolid. Yield: 0.16 g (46%). MP 317-318° C. ¹H NMR (400 MHz, DMSO-d₆): δ12.05 (s, 1H), 8.17 (s, 1H), 8.12 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz,2H), 6.74 (d, J=2.0 Hz, 1H), 6.54 (d, J=2.0 Hz, 1H), 4.61 (s, 2H), 4.02(s, 2H), 3.89 (s, 3H), 3.85 (s, 3H). MS (ES⁺) m/z: 395.09 (M+1).

Example 84. Preparation of2-(3,5-Dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-6-methoxyquinazolin-4(3H)-one

To a suspension of 2-amino-5-methoxy-benzoic acid (5.00 g, 30.0 mmol) inTHF (50 mL) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (7.50 g, 39.0 mmol), 1-hydroxybenzotriazole (4.50 g, 33.0mmol) and 4-methylmorpholine (3.6 mL, 33.0 mmol) and the reactionmixture was stirred at room temperature for 1 hours. Then, 50% aqueousNH₃ (8 mL, 105.0 mmol) was added and the reaction mixture was stirred atroom temperature for 16 hours. Water (100 mL) was added and the productwas extracted with ethyl acetate. Solvent was evaporated in vacuo andthe residue was washed with ether to give 2-amino-5-methoxy-benzamide asa white solid. Yield: 2.62 g (53%).

To a stirred solution of 2-amino-5-methoxy-benzamide (2.62 g, 15.80mmol) and 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benxaldehyde (3.23 g, 16.60mmol) in N,N-dimethyl acetamide (20 mL), were added sodium hydrogensulfite (58.5 wt %, 3.44 g, 19.00 mmol) and p-toluenesulfonic acidmonohydrate (0.60 g, 3.20 mmol) and the reaction mixture was stirred at115° C. for 16 hours. Solvent was evaporated in vacuo, water (50 mL) wasadded, and the separated solid was filtered. The solid was trituratedwith ether to give2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-6-methoxy-3H-quinazolin-4-oneas a white solid. Yield: 3.56 g (66%).

To a suspension of2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-6-methoxy-3H-quinazolin-4-one(1.50 g, 4.41 mmol) in N,N-dimethylformamide (15 mL), carbontetrabromide (1.60 g, 4.85 mmol), and triphenylphosphine (1.30 g, 4.85mmol) were added and the reaction mixture was stirred at roomtemperature for 16 hours. The solvent was evaporated in vacuo and theproduct was purified by the Simpliflash system, using 1-2% methanol inCH₂Cl₂ as eluent, to give2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-6-methoxy-3H-quinazolin-4-oneas a white solid. Yield: 1.77 g (quantitative).

To a suspension of2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-6-methoxy-3H-quinazolin-4-one(1.94 g, 4.80 mmol) in N,N-dimethylformamide (20 mL), pyrrolidine (4 mL)was added and the reaction mixture was stirred at room temperature for16 hours. Solvent was evaporated in vacuo, water (50 mL) was added, andthe separated solid was filtered. The solid was washed with ether togive the title compound as a light brown solid. Yield: 0.30 g (16%). MP201.2-203.1° C. ¹H NMR (400 MHz, CDCl₃): δ 7.73 (m, 4H), 7.39 (m, 1H),3.98 (t, J=6.0 Hz, 3H), 3.94 (s, 3H), 2.97 (t, J=6.0 Hz, 2H), 2.69 (brs, 4H), 2.41 (s, 6H), 1.86 (br s, 4H). MS (ES) m/z: 394.21 (M⁺+1).

Example 85. Preparation of2-(3,5-Dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one

To a solution of 2-amino-4,6-dimethoxy-nicotinamide (0.60 g, 3.00 mmol)and 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (0.59 g, 3.00 mmol)in N,N-dimethylacetamide (8 mL) was added NaHSO₃ (58.5 wt %, 0.59 g,3.30 mmol) and p-TSA (0.22 g, 1.20 mmol). The reaction mixture washeated to 145-148° C. for 16 hours, then cooled to room temperature.N,N-dimethylacetamide was removed under reduced pressure, the residuewas diluted with sodium bicarbonate solution (50 mL), and the solidseparated was filtered and dried under vacuum. The crude compound waspurified by column chromatography (silica gel 230-400 mesh; 5% methanolin dichloromethane as eluent) to give2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-pyrido[2,3-d]pyrimidin-4-oneas a white solid. Yield: 0.50 g (49%).

To a solution of2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-pyrido[2,3-d]pyrimidin-4-one(0.50 g, 1.34 mmol) in anhydrous DMF (6 mL) was added carbontetrabromide (0.53 g, 1.61 mmol) and triphenylphosphine (0.42 g, 1.61mmol). The reaction mixture was stirred at 25° C. for 16 hours. DMF wasremoved under vacuum and dichloromethane (200 mL) was added. The organicphase was washed with water (100 mL), then brine (100 mL), and driedover anhydrous sodium sulfate. Solvent was removed and the residue waswashed with ether (100 mL) to give2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-pyrido[2,3-d]pyrimidin-4-oneas a white solid. Yield: 0.23 g (40%).

A solution of2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-pyrido[2,3-d]pyrimidin-4-one(0.20 g, 0.46 mmol) in pyrrolidine (2 mL) was stirred at roomtemperature for 3 hours. The excess pyrrolidine was removed underreduced pressure, and the residue was purified by column chromatography(silica gel 230-400 mesh; eluting with 2% 2.0 M ammonia in methanolsolution and dichloromethane) to give the title compound as a whitesolid. Yield: 0.17 g (87%). MP 228-230° C. ¹H NMR (400 MHz, CDCl₃): δ10.06 (s, 1H), 7.83 (s, 2H), 6.22 (s, 1H), 4.12 (s, 3H), 4.00 (s, 3H),3.95 (t, J=6.0 Hz, 2H), 2.93 (t, J=6.0 Hz, 2H), 2.64 (m, 4H), 2.37 (s,6H), 1.80 (m, 4H). MS (ES⁺) m/z: 425.19 (M+1).

Example 86. Preparation of2-(3,5-Dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-7-fluoro-5-(pyrrolidin-1-yl)quinazolin-4(3H)-one

A mixture of 2-amino-4,6-difluoro-benzamide (0.96 g, 5.60 mmol),4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (1.09 g, 5.60 mmol),NaHSO₃ (58.5 wt %, 1.00 g, 5.60 mmol) and p-toluenesulfonic acidmonohydrate (1.44 g, 7.06 mmol) in N,N-dimethylacetamide (25 mL) wasstirred at 120° C. for 16 hours, then cooled to room temperature.Solvent was removed under reduced pressure. The residue was diluted withwater (100 mL). The solid separated was filtered and washed with waterand dried under vacuum to give5,7-difluoro-2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-3H-quinazolin-4-oneas a white solid. Yield: 1.55 g (79%).

A mixture of5,7-difluoro-2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-3H-quinazolin-4-one(1.54 g, 4.44 mmol), PPh₃ (1.52 g, 5.78 mmol), and CBr₄ (1.92 g, 5.78mmol) in anhydrous DMF (30 mL) was stirred at room temperature for 36hours. DMF was evaporated under vacuum, water (100 mL) was added, andstirred for 30 minutes. The solid separated was filtered, washed withwater, then ether, and dried under vacuum to give2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-difluoro-3H-quinazolin-4-oneas pale yellow solid. Yield: 1.38 g (crude). This product was used inthe next step without further purification.

A solution of2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-difluoro-3H-quinazolin-4-one(1.38 g, crude) and pyrrolidine (10 mL) was stirred at room temperaturefor 16 hours. Excess pyrrolidine was evaporated, the residue waspurified by column chromatography (silica gel 230-400 mesh; 30-50% ethylacetate in hexanes as eluent). The compound was further purified bypreparative HPLC to give the title compound as a white solid. Yield: 260mg (13% for two steps). MP 206.6-206.8° C. ¹H NMR (400 MHz, DMSO-d₆): δ11.85 (s, 1H), 6.63 (d, J=8 Hz, 1H), 6.51 (d, J=12 Hz, 1H), 3.90 (t, J=4Hz, 2H), 2.83 (t, J=4 Hz, 2H), 2.50 (s, 6H), 2.30 (s, 4H), 1.89 (s, 4H),1.70 (s, 4H).

Example 87. Preparation of5-Chloro-2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-4(3H)-one

To a solution of 2-amino-6-chlorobenzoic acid (2.00 g, 11.65 mmol) inanhydrous THF (20 mL) were added 4-methylmorpholine (1.40 mL, 12.82mmol), HOBT (1.73 g, 12.82 mmol), and EDCI (2.45 g, 12.82 mmol); thereaction mixture was stirred at room temperature for 30 minutes. 50%(v/v) Ammonium hydroxide solution (10 mL, 132.0 mmol) was added and themixture was stirred at room temperature for 23 hours. Solvent wasevaporated to about 20 mL, poured into aqueous NaHCO₃ solution (200 mL)and extracted with ethyl acetate (7×100 mL). The organic phase waswashed with water (3×100 mL), dried (Na₂SO₄), filtered, and evaporated,to give 2-amino-6-chlorobenzamide as a white solid. Yield: 1.65 g (83%).

4-(2-Hydroxyethoxy)-3,5-dimethylbenzaldehyde (0.70 g, 3.58 mmol),2-amino-6-chlorobenzamide (0.60 g, 3.51 mmol), sodium bisulfite (0.71 g,3.86 mmol) and p-toluenesulfonic acid monohydrate (0.133 g, 0.699 mmol)in anhydrous N,N-dimethyl acetamide (14 mL) were heated at 120° C. undernitrogen for 23 hours. The solvent was evaporated and the white solidwas triturated with water (50 mL), filtered, and washed with water (20mL). The solid was dried in vacuo and triturated with Et₂O (20 mL),filtered, and dried to give5-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-oneas a white solid. Yield: 0.77 g, (64%).

To a solution of5-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one(0.40 g, 1.16 mmol) in anhydrous DMF (10 mL) was added carbontetrabromide (0.42 g, 1.27 mmol) and triphenyiphoshine (0.33 g, 1.27mmol). The reaction mixture was stirred at room temperature for 27hours. Solvent was evaporated to dryness in vacuo and the residuetriturated with Et₂O (15 mL)/EtOAc (15 mL) to give2-(4-(2-bromoethoxy)-3,5-dimethylphenyl)-5-chloroquinazolin-4(3H)-one(0.42 g). It was used without further purification. The ¹H NMR indicateda purity of about 45%.

To a solution of2-(4-(2-bromoethoxy)-3,5-dimethylphenyl)-5-chloroquinazolin-4(3H)-one(0.40 g, crude) in anhydrous DMF (10 mL) was added pyrrolidine (0.36 mL,4.35 mmol) and the reaction mixture was stirred at room temperature,under nitrogen, for 25 hours. Solvent was evaporated to dryness invacuo. The residue was triturated with water (50 mL), filtered, and thebrown solid washed with Et₂O (20 mL). The crude material was purified bycolumn chromatography (silica gel 230-400 mesh; 6% methanol indichloromethane as the eluent) and then by reverse-phase HPLC (0.1%aqueous trifluoroacetic acid/acetonitrile as the eluent), to give awhite solid. The solid was dissolved in CH₂Cl₂ (20 mL)/MeOH (4.5 mL),washed with 1 M Na₂CO₃ (4.5 mL) and the organic phase separated. Theaqueous phase was extracted with CH₂Cl₂ (4×20 mL). The combined organicphase was washed with water (10 mL), dried (Na₂SO₄), filtered, andevaporated to give the title compound as a white solid. Yield: 0.091 g(21%, for two steps). MP 179-180° C. ¹H NMR (400 MHz, DMSO-d₆): δ 12.30(br s, 1H), 7.89 (s, 2H), 7.77-7.66 (m, 1H), 7.66-7.60 (m, 1H), 7.47 (d,J=7.42 Hz, 1H), 3.89 (t, J=5.85 Hz, 2H), 2.80 (t, J=5.85 Hz, 2H), 2.53(br s, 4H), 2.30 (s, 6H), 1.68 (br s, 4H). MS (ES+) m/z: 398.11 (100%),400.13, 401.07.

Example 88. Preparation of2-(4-(2-(Azepan-1-yl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

To a suspension of2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one(0.22 g, 0.50 mmol) in DMF (2 mL) was added hexamethyleneimine (azepane)(0.22 mL, 2.0 mmol) and the reaction mixture was stirred at roomtemperature for 17 hours. Saturated aqueous NaHCO₃ solution (2 mL) wasadded and stirred for 2 hours. Water (10 mL) was added and stirred foranother 0.5 hours. The solid was filtered, washed with water, and driedunder vacuum to give the title compound as a white solid. Yield: 0.22 g(95%). MP 198-199° C. ¹H NMR (400 MHz, CD₃OD): δ 7.70 (s, 2H), 6.79 (s,1H), 6.55 (s, 1H), 3.97 (t, J=6.0 Hz, 2H), 3.92 (s, 3H), 3.91 (s, 3H),2.98 (t, J=6.0 Hz, 2H), 2.82 (t, J=5.2 Hz, 4H), 2.37 (s, 6H), 1.72 (m,4H), 1.66 (m, 4H). MS (ES⁺) m/z: 452.27 (M+1). Analysis calculated forC₂₆H₃₃N₃O₄ (451.56), %: C, 69.16; H, 7.37; N, 9.31. Found, %: C, 68.94;H, 6.90; N, 9.30.

Example 89. Preparation of2-(3,5-Dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-difluoroquinazolin-4(3H)-one

To a solution of 2-amino-4,6-difluoro-benzamide (0.80 g, 4.60 mmol) and3,5-dimethyl-4-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (1.14 g, 4.60mmol) in N,N-dimethylacetamide (60 mL) were added sodium hydrogensulfite (58.5 wt %, 1.25 g, 6.9 mmol) and p-toluenesulfonic acidmonohydrate (3.50 g, 18.4 mmol). The reaction mixture was stirred at145° C. for 16 hours under nitrogen atmosphere, then cooled to roomtemperature. Solvent was evaporated under reduced pressure. Water (50mL) was added, followed by saturated aqueous sodium bicarbonate solution(15 mL). The mixture was extracted with CH₂Cl₂ (2×100 mL) and washedwith water. The organic phase was evaporated and the residue was washedwith hexane/ether (90:10, 100 mL). The solid was filtered and driedunder vacuum to give the title compound as a brown solid. Yield: 1.48 g(80%). MP 234-235° C. ¹H NMR (400 MHz, DMSO-d₆): δ 12.36 (s, 1H), 7.90(s, 1H), 7.32 (m, 2H), 3.91 (t, J=4 Hz, 2H), 2.83 (t, J=4 Hz, 2H), 2.55(s, 4H), 2.31 (s, 6H), 1.70 (s, 4H).

Example 90. Preparation of2-(4-(2-(Azetidin-1-yl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

To a suspension of2-[4-(2-bromoethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one(216 mg, 0.50 mmol) in DMF (5 mL) was added azetidine (154 mg, 2.70mmol). The reaction mixture was stirred at room temperature for 2 days.The solid was collected by filtration, washed with methanol, ethylacetate, and water, and dried under vacuum to give the title compound asa white solid. Yield: 58 mg (28%). MP 204-205° C. ¹H NMR (400 MHz,DMSO-d₆): δ 7.85 (s, 2H), 6.71 (d, J=2.4 Hz, 1H), 6.49 (d, J=2.4 Hz,1H), 3.86 (s, 3H), 3.81 (s, 1H), 3.70 (t, J=6.0 Hz, 2H), 3.18 (t, J=6.8Hz, 4H), 2.70 (t, J=6.0 Hz, 2H), 2.26 (s, 6H), 1.97 (m, 2H). MS (ES)m/z: 410.20 (M+1) (100%).

Example 91. Preparation ofN-(1-(2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)azetidin-3-yl)acetamide

To a solution of N-(1-benzhydryl-azetidin-3-yl)-acetamide (1.00 g, 3.57mmol) in ethanol (20 mL) were added palladium hydroxide on carbon (20 wt%, 0.20 g) and concentrated HCl (0.6 mL). The reaction mixture washydrogenated at 50 psi at 40° C. for 2 hours. Then, the solid wasfiltered and washed with methanol (50 mL). The filtrate was collected;the solvent was evaporated to give N-azetidin-3-yl-acetamide as a greengummy material. Yield: 0.40 g (crude). This product was used in nextstep without further purification.

To a suspension of N-azetidin-3-yl-acetamide (0.30 g crude, 1.99 mmol)and2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one(0.43 g, 1.00 mmol) in anhydrous DMF (10 mL) was added triethylamine (3mL). The reaction mixture was stirred at room temperature for 3 daysunder nitrogen. Solvent was evaporated under reduced pressure, water (50mL) was added, and the precipitated solid was filtered. The aqueousphase was extracted with ethyl acetate (2×100 mL). The organic phase wasdried over anhydrous Na₂SO₄. Solvent was evaporated, and crude compoundwas purified by the Simpliflash system (0-5% 7 N ammonia in methanol andCH₂Cl₂ as eluent) to give the title compound as a white solid. Yield:0.30 g (63%). MP 111.8-113.6° C. ¹H NMR (400 MHz, CDCl₃): δ 9.60 (br s,1H), 7.69 (s, 2H), 6.82 (d, J=2.34 Hz, 1H), 6.46 (d, J=2.34 Hz, 1H),6.10 (d, J=7.81 Hz, 1H), 4.71-4.44 (m, 1H), 3.97 (s, 3H), 3.93 (s, 3H),3.85-3.67 (m, 4H), 3.26-3.13 (m, 2H), 2.90 (t, J=5.46 Hz, 2H), 2.36 (s,6H), 2.01 (s, 3H). MS (ES⁺) m/z: 467.20 (M+1).

Example 92. Preparation of2-(3,5-Dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-diisopropoxyquinazolin-4(3H)-one

To a solution of2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-diisopropoxy-3H-quinazolin-4-one(0.73 g, 1.70 mmol) in DMF (10 mL) were added PPh₃ (0.49 g, 1.87 mmol)and CBr₄ (0.62 g, 1.87 mmol). The reaction mixture was stirred at roomtemperature for 16 hours. Then, solvent was removed under reducedpressure. The residue was triturated with ether and ethyl acetate. Thesolid was dried and purified by the Simpliflash system (2% methanol inCH₂Cl₂ as eluent) to give2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-diisopropoxy-3H-quinazolin-4-oneas a white solid. Yield: 0.39 g (47%).

To a solution of2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-diisopropoxy-3H-quinazolin-4-one(0.39 g, 0.79 mmol) in DMF (10 mL) was added pyrrolidine (0.45 g, 6.37mmol). The reaction mixture was stirred at room temperature for 4 hours.Then, water was added and product was extracted with ethyl acetate(2×200 mL). The combined organic phase was washed with water, thenbrine, and dried over anhydrous Na₂SO₄. Solvent was evaporated to givethe title compound as a white solid. Yield: 0.32 g (83%). MP 65-68° C.¹H NMR (400 MHz, CDCl₃): δ 9.05 (br s, 1H), 7.63 (s, 2H), 6.78 (s, 1H),6.42 (s, 1H), 4.70 (m, 1H), 4.63 (m, 1H), 3.94 (m, 2H), 2.94 (m, 2H),2.64 (br s, 4H), 2.38 (s, 6H), 1.84 (m, 4H), 1.46 (m, 3H), 1.42 (m, 3H).MS (ES) m/z: 480.29 (M+1).

Example 93. Preparation of8-Chloro-2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-4(3H)-one

To a solution of 2-amino-3-chloro-benzoic acid (2.57 g, 15.0 mmol) inTHF (100 mL) were added EDCI (3.16 g, 16.5 mmol), HOBt (2.23 g, 16.5mmol) and N-methylmorpholine (1.67 g, 16.5 mmol). The reaction mixturewas stirred at room temperature for 20 minutes then 50% (v/v) aq. NH₄OHsolution (4.2 mL, 60.0 mmol) was added. The mixture was stirred for 20hours at room temperature. Solvent was evaporated and the residue wastaken in ethyl acetate (200 mL). Water (100 mL) was added. The organicphase was separated; the aqueous phase was extracted with ethyl acetate(200 mL). The combined organic phase was washed with water (100 mL),then brine (100 mL), and dried over anhydrous sodium sulfate. Solventwas evaporated and dried under vacuum to give 2-amino-3-chloro-benzamideas a white solid. Yield: 2.07 g (81%).

To a solution of 2-amino-3-chloro-benzamide (0.85 g, 5.00 mmol) and3,5-dimethyl-4-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (1.23 g, 5.00mmol) in N,N-dimethylacetamide (20 mL) were added sodium hydrogensulfite (58.5 wt %, 1.37 g, 7.50 mmol) and p-toluenesulfonic acidmonohydrate (3.80 g, 20.0 mmol). The reaction mixture was stirred at140° C. for 16 hours under nitrogen, then cooled to room temperature.Solvent was evaporated under reduced pressure. Water (100 mL) was added,and the mixture was neutralized, to pH approximately 8 with 2 N aqueousNaOH solution. The separated solid was filtered, washed with water (50mL), and dried under vacuum. Crude compound was purified by theSimpliflash system (0-5% methanol in CH₂Cl₂ and then 5% 7.0 M ammonia inmethanol and CH₂Cl₂ as eluent) to give the title compound as a brownsolid. Yield: 0.49 g (25%). MP 216-217° C. ¹H NMR (400 MHz, DMSO-d₆): δ8.07 (d, J=7.81 Hz, 1H), 8.01-7.87 (m, 3H), 7.43 (t, J=7.81 Hz, 1H),3.89 (t, J=5.85 Hz, 2H), 2.81 (t, J=5.85 Hz, 2H), 2.53 (br s, 4H), 2.30(s, 6H), 1.75-1.60 (m, 4H). MS (ES+) m/z 398.11 (100%), 400.13 (40%).

Example 94. Preparation of2-(3,5-Dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-dimethylquinazolin-4(3H)-one

Chloral hydrate (15.29 g, 92.42 mmol) was taken in water (335 mL).Sodium sulfate (78.14 g, 550.13 mmol) was added at room temperature.Then, a suspension of hydroxylamine hydrochloride (18.35 g, 264.06mmol), 3.5-dimethylaniline (10.0 g, 82.52 mmol) and concentratedhydrochloric acid (36.5%, 10 mL) was added. The mixture was heated at45° C. for 1.5 hours, then 75° C. for 1 hour. The reaction mixture wascooled to room temperature. The precipitated brown solid was filteredand washed with cold water (50 mL) and hexane (50 mL). The crudecompound was dried under vacuum to giveN-(3,5-dimethyl-phenyl)-2-hydroxyimino-acetamide as a brown solid.Yield: 13.7 g (86%). The crude compound was used in the next stepwithout further purification.

N-(3,5-Dimethyl-phenyl)-2-hydroxyimino-acetamide (13.7 g, 71.3 mmol) wasadded to concentrated sulfuric acid (70 mL) in a 250 mL flask. Thereaction mixture was then heated at 80° C. for 30 minutes, then cooledto room temperature, and poured into ice-water (200 mL). Theprecipitated solid was filtered and washed with water (100 mL) and driedunder vacuum to give 4,6-dimethyl-1H-indole-2,3-dione as an orangesolid. Yield: 5.53 g (44%).

To a heated (70° C. bath temperature) deep red solution of4,6-dimethyl-1H-indole-2,3-dione (1.00 g, 5.71 mmol) in 33% aqueoussodium hydroxide (35 mL) was added 35% hydrogen peroxide (3.33 g, 34.3mmol) over a period of 5 minutes. The reaction mixture was heated foranother 15 min, then cooled to room temperature, and ice was added. ThepH was adjusted to approximately 8 with concentrated HCl at 0° C. andacidified further to pH approximately 6 with glacial acetic acid. Thesolid precipitated was filtered, washed well with cold water, and driedunder vacuum at 40° C. overnight to obtain 2-amino-4,6-dimethyl-benzoicacid as a pale brown solid. Yield: 0.35 g (37%).

To a solution of 2-amino-4, 6-dimethyl-benzoic acid (0.35 g, 2.08 mmol)in anhydrous THF (10 mL) was added EDCI (0.80 g, 4.17 mmol), HOBt (0.80g, 5.22 mmol) and N-methyl-mopholine (0.7 mL, 6.24 mmol). The reactionmixture was stirred at room temperature for 30 minutes, then ammoniumhydroxide (50% v/v, 2.5 mL) was added. The mixture was stirred at roomtemperature for 17 hours. The solvent was removed under reducedpressure. Water (50 mL) was added, and the mixture was extracted withdichloromethane (2×100 mL). The combined organic phase was washed withwater, and dried over anhydrous Na₂SO₄. Removal of the solvent gave thecrude product. The crude product was purified by column chromatography(silica gel 230-400 mesh; 3% methanol in dichloromethane as eluent) togive 2-amino-4,6-dimethyl-benzamide. Yield: 0.20 g (59%).

To a solution of 2-amino-4,6-dimethyl-benzamide (0.20 g, 1.22 mmol) and3,5-dimethyl-4-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (0.36 g, 1.46mmol) in N,N-dimethylacetamide (10 mL) was added NaHSO₃ (58.5 wt %, 0.55g, 3.05 mmol) and p-TSA (0.46 g, 2.44 mmol). The reaction mixture washeated to 110° C. for 2 hours, then cooled to room temperature.N,N-dimethylacetamide was removed under reduced pressure, the residuewas diluted with sodium bicarbonate solution (50 mL), and the solidseparated was filtered and dried under vacuum. The crude compound waspurified by column chromatography (silica gel 230-400 mesh; 6% methanolin dichloromethane as eluent) to give the title compound as a whitesolid. Yield: 0.145 g (30%). MP 181-182° C. ¹H NMR (400 MHz, DMSO-d₆): δ10.62 (s, 1H), 7.75 (s, 2H), 7.44 (s, 1H), 7.03 (s, 1H), 3.95 (t, J=6.0Hz, 2H), 2.94 (t, J=6.0 Hz, 2H), 2.85 (s, 3H), 2.65 (s, 4H), 2.44 (s,3H), 2.39 (s, 6H), 1.84 (s, 4H). MS (ES⁺) m/z: 392.13 (M+1).

Example 95. Preparation of2-(2-(4-(6,8-Dimethoxy-1-oxo-1,2-dihydroisoquinolin-3-yl)-2,6-dimethylphenoxy)ethyl)isoindoline-1,3-dione

To a suspension of3-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-6,8-dimethoxy-2H-isoquinolin-1-one(0.80 g, 2.16 mmol), isoindole-1,3-dione (0.35 g, 2.38 mmol), andtriphenylphosphine (0.85 g, 3.25 mmol) in THF (30 mL), was added diethylazodicarboxylate (0.56 g, 3.25 mmol) and the reaction mixture wasstirred at room temperature for 16 hours. The solvent was evaporated invacuo and the residue was washed with ether to give the title compoundas an off-white solid. Yield: 1.11 g (crude). ¹H NMR (400 MHz, CDCl₃): δ8.34 (s, 1H), 7.89 (m, 2H), 7.77 (m, 2H), 7.21 (s, 2H), 6.49 (br s, 2H),6.44 (s, 1H), 4.16 (m, 2H), 4.08 (m, 2H), 3.97 (s, 3H), 3.89 (s, 3H),2.25 (s, 6H). MS (ES) m/z: 499.06 (M+1) (100%).

Example 96. Preparation of2-(3,5-Dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-diisopropoxypyrido[2,3-d]pyrimidin-4(3H)-one

To a suspension of2-amino-4-hydroxy-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methylester (7.0 g, 38.04 mmol), 2-iodopropane (14.22 g, 83.69 mmol), andK₂CO₃ (11.56 g, 83.69 mmol) in DMF (200 mL), was heated at 60° C. for 48hours, then cooled to the room temperature and filtered. Water (400 mL)was added to the filtrate and the product was extracted with ethylacetate (3×200 mL). The combined organic layer was washed with water,then brine, dried over Na₂SO₄, and evaporated to give crude product. Thecrude product was purified by Simpliflash, using 10% ethyl acetate inhexane, to give 2-amino-4, 6-diisopropoxy-nicotinic acid methyl ester asa colorless oil. Yield: 1.30 g (13%). ¹H NMR (400 MHz, DMSO-d₆): δ 6.91(s, 2H), 5.57 (s, 1H), 5.19 (m, 1H), 4.59 (m, 1H), 3.66 (s, 3H), 1.23(d, J=2.0 Hz, 6H), 1.21 (d, J=1.2 Hz, 6H).

To the solution of 2-amino-4, 6-diisopropoxy-nicotinic acid methyl ester(1.6 g, 5.97 mmol) in methanol (9.0 mL) and water (1.0 mL), was addedlithium hydroxide (750 mg, 17.91 mmol). The reaction mixture was heatedto 50° C. for 8 hours. The solvent was removed; the residue was dilutedwith water and neutralized with 2 N HCl. The product was extracted withethyl acetate (3×100 mL). The combined organic layer was washed withwater, then brine, dried over Na₂SO₄, and evaporated, to give crude2-amino-4,6-diisopropoxy-nicotinic acid as a light yellow solid. Yield:1.48 g (98%, crude).

To a solution of 2-amino-4,6-diisopropoxy-nicotinic acid (1.48 g, 5.83mmol) in THF (30 mL) were added EDCI (1.34 g, 6.99 mmol), HOBt (0.94 g,6.99 mmol), NMM (0.70 g, 6.99 mmol) and liquid NH₃ (10 mL). Then, thereaction mixture was stirred at room temperature for 24 hours. Then,water (100 mL) was added and the products were extracted with ethylacetate (2×200 mL). The combined organic phase was washed with water,then brine, and dried over anhydrous Na₂SO₄. Removal of solvent gavecrude 2-amino-4,6-diisopropoxy-nicotinamide as a yellow oil. Yield: 450mg (26%, crude).

To a solution of 2-amino-4,6-diisopropoxy-nicotinamide (450 mg, 1.78mmol) and 3,5-dimethyl-4-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (440mg, 1.78 mmol) in N,N-dimethyl acetamide (10 mL) were added NaHSO₃ (790mg, 4.44 mmol) and p-TSA (845 mg, 4.44 mmol). The reaction mixture washeated at 120° C. for 16 hours, then cooled to room temperature. Thesolvent was removed under reduced pressure. Then, water (100 mL) wasadded and stirred for 30 min at room temperature. The separated solidswere filtered and dried to give crude product, which was purified by theSimpliflash system, using 2% methanol in dichloromethane, to give ayellow oil, which dissolved in ether. 2N HCl in ether was added, and theseparated solids were filtered and dried to give the hydrochloride saltof the title compound as a yellow solid. Yield: 59 mg (6%). ¹H NMR (400MHz, DMSO-d₆): δ 10.7 (br s, 1H), 7.88 (s, 2H), 6.31 (s, 1H), 5.41 (m,1H), 4.80 (m, 1H), 4.14 (t, J=4.8 Hz, 2H), 3.61 (m, 2H), 3.16 (m, 4H),2.34 (s, 6H), 2.03 (m, 2H), 1.91 (m, 2H), 1.32 (s, 6H), 1.30 (s, 6H). MS(ES) m/z: 481.18 (M+1).

Example 97. Preparation of(S)-2-(3,5-Dimethyl-4-((5-oxopyrrolidin-2-yl)methoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

To a solution of (S)-5-(hydroxymethyl)pyrrolidin-2-one (3.85 g, 33.5mmol) in acetonitrile (60 mL) under nitrogen was added PPh₃ (9.16 g,34.8 mmol). The mixture was cooled to 0° C. and CBr₄ (11.55 g, 34.8mmol) added dropwise as a solution in acetonitrile (40 mL) over 15minutes. Then, the reaction mixture was warmed to room temperature andstirred for 18 hours. The mixture was then concentrated and heptane (100mL) and water (100 mL) added. After stirring for 1 hour, the solids werefiltered and washed with 1:1 heptane/water (100 mL). The filtrate layerswere separated and the aqueous layer extracted with Et₂O (2×100 mL) andCHCl₃ (2×100 mL). The combined organic phase was dried over anhydrousNa₂SO₄, filtered, concentrated, and purified by silica gelchromatography, eluting with 100% CHCl₃ to 10% MeOH/CHCl₃, to afford(S)-5-(bromomethyl)pyrrolidin-2-one as a white solid (3.15 g, 53%).

To a solution of 4-hydroxy-3,5-dimethylbenzaldehyde (2.65 g, 17.7 mmol)in DMF (100 mL) was added K₂CO₃ (3.66 g, 26.6 mmol). The mixture wasstirred at room temperature under nitrogen for 30 minutes. Then, asolution of (S)-5-(bromomethyl)pyrrolidin-2-one (3.15 g, 17.7 mmol) inDMF (100 mL) was added, and the mixture heated at reflux for 16 hours.The mixture was then concentrated, ethyl acetate (250 mL) added, and theorganic phase washed sequentially with water (2×150 mL), and brine (200mL), dried (Na₂SO₄), filtered, and concentrated. The residue waspurified by silica gel chromatography, eluting with 100% ethyl acetateto 10% MeOH/ethyl acetate, followed by a second chromatography, elutingwith 1:1 CH₂Cl₂/92:7:1 CHCl₃/MeOH/concentrated NH₄OH to 100% 92:7:1CHCl₃/MeOH/concentrated NH₄OH, to afford(S)-3,5-dimethyl-4-((5-oxopyrrolidin-2-yl)methoxy)benzaldehyde as awhite solid (0.200 g, 5%).

A mixture of(S)-3,5-dimethyl-4-((5-oxopyrrolidin-2-yl)methoxy)benzaldehyde (0.200 g,0.81 mmol), 2-amino-4,6-dimethoxybenzamide (0.159 g, 0.81 mmol), NaHSO₃(0.093 g, 0.89 mmol), and p-TsOH (0.015 g, 0.08 mmol) in DMA (10 mL) washeated at 150° C. for 48 hours. The reaction mixture was cooled to roomtemperature, diluted with ethyl acetate (200 mL), washed with water(2×200 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. Theresidue was purified by flash chromatography on silica gel, eluting with1:1 CH₂Cl₂/92:7:1 CHCl₃/MeOH/concentrated NH₄OH to 100% 92:7:1CHCl₃/MeOH/concentrated NH₄OH to 6:3:1 CHCl₃/MeOH/concentrated NH₄OH, toafford the title compound as an off-white solid (0.108 g, 31%). ¹H NMR(300 MHz, DMSO-d₆): δ 11.85 (s, 1H), 7.79-7.91 (m, 3H), 6.74 (d, J=2.2Hz, 1H), 6.52 (d, J=2.2 Hz, 1H), 3.88-3.94 (m, 4H), 3.84 (s, 3H),3.63-3.75 (m, 2H), 2.30 (s, 6H), 2.09-2.27 (m, 3H), 1.91-2.00 (m, 1H).APCI MS m/z 424 [M+H]⁺.

Example 98. Preparation of2-(4-((4-Isopropylpiperazin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

To a mixture of 4-(bromoethyl)benzaldehyde (0.200 g, 1.0 mmol) and K₂CO₃(0.277 g, 2.0 mmol) in DMF (5 mL) was added N-isopropylpiperazine (0.129g, 1.0 mmol) and the reaction was stirred at room temperature for 5hours, then concentrated in vacuo. The resulting mixture was dilutedwith H₂O and extracted with EtOAc. The organics were washed with brine,dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo toafford 4-((4-Isopropylpiperazin-1-yl)methyl)benzaldehyde (0.240 g, 97%).

A mixture of 4-((4-isopropylpiperazin-1-yl)methyl)benzaldehyde (0.240 g,0.97 mmol), NaHSO₃ (0.155 g, 1.50 mmol), and p-TsOH (0.019 g, 0.10 mmol)was added to a solution of 2-amino-4,6-dimethoxybenzamide (0.190 g, 0.97mmol) in DMA (7 mL). The reaction was stirred at 130° C. overnight.Then, the mixture was diluted with H₂O and extracted with CH₂Cl₂. Theorganics were washed with brine, dried over anhydrous Na₂SO₄, filtered,and concentrated in vacuo. Purification by flash chromatography onsilica gel, eluting with 2% to 10% MeOH/CH₂Cl₂, afforded the titlecompound (0.122 g, 30%) as a light yellow solid. ¹H NMR (300 MHz,DMSO-d₆): δ 12.02 (s, 1H), 8.12 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz,2H), 6.74 (s, 1H), 6.53 (s, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.51 (s,2H), 2.54-2.71 (m, 1H), 2.27-2.44 (m, 8H), 0.95 (d, J=6.4 Hz, 6H). ESIMS m/z 423 [M+H]⁺.

Example 99. Preparation ofN-(1-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)benzyl)piperidin-4-yl)-N-isopropylacetamide

To a mixture of 4-(bromoethyl)benzaldehyde (0.840 g, 4.2 mmol) and K₂CO₃(1.75 g, 12.6 mmol) in DMF (15 mL) was addedN-isopropyl-N-(piperidin-4-yl)acetamide (0.92 g, 4.2 mmol) and thereaction was stirred at room temperature 5 hours, then concentrated invacuo. The resulting mixture was diluted with H₂O and extracted withEtOAc. The organics were washed with brine, dried over anhydrous Na₂SO₄,filtered, and concentrated in vacuo. Purification by flashchromatography on silica gel, eluting with 1% to 10% MeOH/CH₂Cl₂,afforded N-(1-(4-formylbenzyl)piperidin-4-yl)-N-isopropylacetamide(0.770 g, 61%).

A mixture of N-(1-(4-formylbenzyl)piperidin-4-yl)-N-isopropylacetamide(0.770 g, 2.5 mmol), NaHSO₃ (0.350 g, 3.3 mmol), and p-TsOH (0.100 g,0.51 mmol) was added to a solution of 2-amino-4,6-dimethoxybenzamide(0.500 g, 2.5 mmol) in DMA (20 mL). The reaction was stirred at 130° C.for 5 hours and concentrated in vacuo. The residue was diluted with H₂Oand saturated NaHCO₃, then extracted with CH₂Cl₂. The organics werewashed with brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated in vacuo. Purification by flash chromatography on silicagel, eluting with 1% to 10% MeOH/CH₂Cl₂, afforded the title compound(0.670 g, 56%) as a light yellow solid. ¹H NMR (300 MHz, DMSO-d₆): δ12.02 (s, 1H), 8.13 (d, J=8.1 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 6.74 (d,J=1.9 Hz, 1H), 6.54 (d, J=2.0 Hz, 1H), 3.85-3.95 (m, 7H), 3.43-3.71 (m,3H), 2.55-3.00 (m, 3H), 1.97-2.09 (m, 5H), 1.70-1.77 (m, 1H), 1.58-1.61(m, 1H), 1.25-1.30 (m, 4H), 1.11-1.13 (m, 3H). ESI MS m/z 479 [M+H]⁺.

Example 100. Preparation of2-(4-((4-(Isopropylamino)piperidin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

A solution of2-(4-((4-isopropylpiperazin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one(0.470 g, 0.98 mmol) in 2N HCl (20 mL) was refluxed for 3 days. Theresulting mixture was basified with 2N NaOH and extracted with CH₂Cl₂.The organics were washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. Purification by flash chromatographyon silica gel, eluting with 30% to 100% of 92:7:1CHCl₃/MeOH/concentrated NH₄OH in CH₂Cl₂, afforded the title compound(0.090 g, 21%) as a light yellow solid. ¹H NMR (300 MHz, DMSO-d₆): δ8.12 (d, J=8.3 Hz, 2H), 7.42 (d, J=8.3 Hz, 2H), 6.73 (d, J=2.3 Hz, 1H),6.53 (d, J=2.3 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.50 (s, 2H),2.86-2.92 (m, 1H), 2.73-2.77 (m, 2H), 1.85-2.01 (m, 2H), 1.72-1.77 (m,2H), 1.09-1.38 (m, 4H), 0.94 (d, J=6.2 Hz, 6H). ESI/APCI MS m/z 437[M+H]⁺.

Example 101. Preparation of2-(4-((1H-Tetrazol-5-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

To a solution of 4-cyanomethyl benzoic acid methyl ester (2.63 g, 15mmol) in anhydrous toluene (100 mL) was added sodium azide (1.95 g, 30mmol) and triethylamine hydrochloride (4.13 g, 30 mmol). The reactionmixture was stirred at 100° C. for 24 hours under nitrogen. The reactionmixture was cooled to room temperature, then extracted with water (2×100mL). The aqueous layer was acidified with concentrated HCl to pHapproximately 4. The white solid was filtered off, washed with water,and dried under vacuum at 40° C. overnight, to givemethyl-4-(1H-tetrazol-5-ylmethyl)benzoate (2.88 g, 88%) as an off-whitesolid.

Lithium aluminium hydride (0.142 g, 3.75 mmol) was taken in a dry,three-necked flask, fitted with a reflux condenser. Anhydrous ether (10mL) was added. A solution of methyl-4-(1H-tetrazol-5-ylmethyl)benzoate(0.654 g, 3.0 mmol) in anhydrous THF (5 mL) was added dropwise. Afterthe addition was complete, the mixture was heated to reflux for 2 hours.Then, the reaction mixture was cooled to 0° C. and quenched by cautiousaddition of water (10 mL) and 15% sodium hydroxide solution (10 mL). Thereaction mixture was stirred for 30 minutes and then allowed to warm toroom temperature. The aqueous phase was acidified to pH 4 and left for 2days. A white precipitate was formed and filtered off, washed withwater, and dried under vacuum, to give[4-(1H-tetrazol-5-ylmethyl)-phenyl]-methanol as a white solid. Yield:0.290 g (51%).

IBX (0.437 g, 1.562 mmol) was dissolved in anhydrous DMSO (5 mL) and[4-(1H-tetrazol-5-ylmethyl)-phenyl]methanol (0.270 g, 1.562 mmol) wasadded. The reaction mixture was stirred at room temperature undernitrogen for 4 hours. Water (20 mL) was added. The white precipitate wasfiltered off, washed with water, and dried under vacuum. The crudecompound was mixed with methanol (20 mL) and stirred for 30 minutes,before being filtered. The filtrate was concentrated to give4-(1H-tetrazol-5ylmethyl)-benzaldehyde as a white solid. Yield: 0.267 g(99%). To a solution of 2-amino-4,6-dimethoxybenzamide (0.157 g, 0.8mmol) in N,N-dimethyl acetamide (5 mL) were added4-(1H-tetrazol-5ylmethyl)-benzaldehyde (0.260 g, 1.4 mmol), sodiumhydrogen sulfite (58.5%, 0.159 g, 0.88 mmol) and p-toluenesulfonic acid(19 mg, 0.08 mmol). The reaction mixture was stirred at 150° C. for 3 h,then cooled to room temperature. Water (40 mL) was then added. A yellowprecipitate was formed and filtered off, washed with water, and smallamount of methanol. It was triturated with 10% methanol in ether to give0.107 g of solid, which was further purified by preparative HPLC, togive the title compound (0.082 g, 28%) as a white solid. MS (ES) m/z:365.1 (M+1). MP 295-296° C.

Example 102. Preparation of1-(2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)pyrrolidine-2,5-dione

To a solution of2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one(0.50 g, 1.35 mmol) in anhydrous THF (20 mL) were added triphenylphosphine (0.53 g, 2.02 mmol), pyrrolidine-2,5-dione (0.20 g, 2.02mmol), and N,N-diisopropylethyl amine (0.44 g, 3.38 mmol). To thisstirred solution was added diethylazodicarboxylate (0.35 g, 2.02 mmol).The reaction mixture was stirred at room temperature for 8 hours undernitrogen. Ethyl acetate (400 mL) was added. The organic phase wasseparated, washed with water (100 mL), then brine (100 mL), and driedover anhydrous Na₂SO₄. The solvent was removed under reduced pressure.The crude material was purified by the Simpliflash system (4:96methanol:CH₂Cl₂ as eluent) to give the title compound as a white solid.Yield: 0.3 g. (49%). ¹H NMR (400 MHz, CDCl₃): δ 9.30 (br s, 1H), 7.66(s, 2H), 6.82 (d, J=2.4 Hz, 1H), 6.46 (d, J=1.6 Hz, 1H), 3.99 (s, 3H),3.97 (s, 3H), 3.92 (s, 4H), 2.78 (s, 4H), 2.31 (s, 6H). MS (ES) m/z:452.51 (M+1) (100%).

Example 103. Preparation of7-(2-(Benzyloxy)ethoxy)-5-methoxy-2-(pyridin-4-yl)quinazolin-4(3H)-one

To a stirred solution of 2-amino-4,6-difluoro-benzamide (0.50 g, 2.9mmol) and pyridine-4-carbaldehyde (0.35 g, 3.2 mmol) inN,N-dimethylacetamide (10 mL) were added sodium hydrogen sulfite (0.63g, 3.5 mmol) and p-toluenesulfonic acid (0.06 g, 0.3 mmol); the reactionmixture was stirred at 115° C. for 16 hours. The solvent was evaporatedin vacuo, water was added, and the precipitated solid was filtered offto obtain 5,7-difluoro-2-pyridin-4-yl-3H-quinazolin-4-one as a yellowsolid, which was used in the next step without further purification.Yield: 0.4 g (53%).

To a suspension of 5,7-difluoro-2-pyridin-4-yl-3H-quinazolin-4-one (0.20g, 0.80 mmol) in DMF (3 mL) was added sodium methoxide in methanol (0.43g, 8.0 mmol) and the reaction mixture was stirred at room temperaturefor 16 hours. Water was added, the mixture was acidified with aceticacid to pH approximately 4-5, and the precipitated solid was filteredoff to obtain 7-fluoro-5-methoxy-2-pyridin-4-yl-3H-quinazolin-4-one as ayellowish solid. Yield: 0.20 g (83%).

To a solution of 2-benzyloxy-ethanol (2 mL) in dimethyl sulfoxide (3 mL)was added sodium hydride (0.30 g, 7.4 mmol) in portions, and thereaction mixture was stirred at room temperature for 45 minutes. To thismixture was added 7-fluoro-5-methoxy-2-pyridin-4-yl-3H-quinazolin-4-one(0.20 g, 0.74 mmol) and the reaction mixture was heated at 80° C. for 16hours. Water was added, the mixture was acidified with acetic acid to pHapproximately 4-5, and the precipitated solid was filtered off, toobtain a crude product, which was purified by preparative HPLC to obtainthe title compound as a light yellow solid. Yield: 0.12 g (40%). MP228.2-229.9° C. ¹H NMR (400 MHz, DMSO-d₆): δ 12.29 (s, 1H), 8.77 (d,2H), 8.08 (d, 2H), 7.36 (m, 5H), 6.82 (s, 1H), 6.62 (s, 1H), 4.58 (s,2H), 4.32 (t, 2H), 3.87 (s, 3H), 3.83 (t, 2H). MS (ES⁺) m/z: 404.51(M+1).

Example 104. Preparation of2-(2,6-Dimethylpyridin-4-yl)-5,7-dimethoxyquinazolin-4(3H)-one

A solution of 2,6-lutidine N-oxide (24.0 g, 0.20 mol) in anhydrousdichloromethane (400 mL) was added to trimethyloxonium tetrafluoroborate(29.6 g, 0.20 mol) at room temperature under nitrogen atmosphere and thereaction mixture was stirred at room temperature for 3 hours. Themixture was concentrated in vacuo to give the crude product,1-methoxy-2,6-dimethyl-pyridinium tetrafluoroborate.

The crude product was dissolved in MeOH (300 mL) and heated to refluxunder nitrogen. Then, a solution of ammonium persulfate (14.2 g, 0.06mol) in water (57 mL) was added. The mixture was stirred under refluxfor 16 hours; TLC showed completion of the reaction. Half of the solventwas removed in vacuo, then quenched with 10% aqueous NaOH solution to pH7, and evaporated to dryness in vacuo. The residue was dissolved inmethanol and filtered, the filtrate was concentrated in vacuo, and thecrude compound was purified by column chromatography (silica gel 230-400mesh; 5-15% methanol in CH₂Cl₂ as eluent) to give4-hydroxymethyl-2,6-dimethylpyridine as a white solid. Yield: 11.0 g(40.0%).

4-Hydroxymethyl-2,6-dimethylpyridine (1.00 g, 7.28 mmol) was dissolvedin ethanol (20 mL), and activated MnO₂ (2.24 g, 21.8 mmol) was added;the reaction mixture was refluxed for 17 hours. The mixture was cooledand concentrated, purified by column chromatography (silica gel 230-400mesh; 20% ethyl acetate in hexanes as eluent) to give2,6-dimethyl-4-pyridinecarboxaldehyde as a yellow oil. Yield: 0.14 g(14%).

To a solution of 2,6-dimethylpyridine-4-carbaldehyde (0.14 g, 1.00 mmol)in N,N-dimethyl acetamide (10 mL) were added2-amino-4,6-dimethoxybenzamide (0.20 g, 1.00 mmol), sodium hydrogensulfite (0.21 g, 2.00 mmol), and p-toluenesulfonic acid (0.28 g, 1.50mmol). The reaction mixture was stirred at 110° C. for 16 hours undernitrogen. After cooling to room temperature, solvent was evaporatedunder reduced pressure. The residue was dissolved in ethyl acetate,washed with saturated NaHCO₃ solution (30 mL), water (30 mL), and brine(30 mL), and dried over anhydrous sodium sulfate. Solvent wasevaporated, and the residue was purified by column chromatography(silica gel 230-400 mesh; 2-5% methanol in dichloromethane as eluent) togive the title compound as a yellow solid. Yield: 0.030 g (10%). MP291-292° C. ¹H NMR (400 MHz, CDCl₃): δ 9.86 (br s, 1H), 7.60 (s, 2H),6.87 (d, J=2.2 Hz, 1H), 6.53 (d, J=2.2 Hz, 1H), 3.99 (s, 3H), 3.95 (s,3H), 2.66 (s, 6H). MS (ES) m/z: 312.50 (M+1) (100%).

Example 105. Preparation of2-(2,6-Dimethylpyridin-4-yl)-5-methoxy-7-(2-methoxyethoxy)quinazolin-4(3H)-one

To a suspension of 2,6-dimethyl-pyridin-4-yl)-methanol (1.00 g, 7.30mmol) in acetonitrile (20 mL),1,2-benziodexol-3(1H)-one-1-hydroxy-1-oxide (IBX) (2.00 g, 7.30 mmol)was added and the reaction mixture was refluxed for 6 hours. The solidwas filtered off and washed with acetonitrile. The filtrate wasevaporated in vacuo to give 2,6-dimethyl-pyridine-4-carbaldehyde as abrown liquid. Yield: 0.81 g (82%).

To a stirred solution of 2-amino-4,6-difluoro-benzamide (1.03 g, 6.00mmol) and 2,6-dimethyl-pyridine-4-carbaldehyde (0.81 g, 6.00 mmol) inN,N-dimethyl acetamide (15 mL), sodium hydrogen sulfite (58.5 wt %, 1.31g, 7.20 mmol), and p-toluenesulfonic acid monohydrate (0.11 g, 0.60mmol) were added and the reaction mixture was stirred at 115° C. for 16hours. The solvent was evaporated in vacuo, water was added, and theprecipitated solid was filtered, to give2-(2,6-dimethyl-pyridin-4-yl)-5,7-difluoro-3H-quinazolin-4-one as ayellow solid, which was used in the next step without furtherpurification. Yield: 0.72 g (42%).

To a suspension of2-(2,6-dimethyl-pyridin-4-yl)-5,7-difluoro-3H-quinazolin-4-one (0.72 g,2.51 mmol) in DMF (10 mL), a solution of sodium methoxide in methanol(25 wt %, 1.36 g, 25.1 mmol) was added and the reaction mixture wasstirred at room temperature for 16 h. Water was added, the mixture wasacidified to pH approximately 4-5 with acetic acid, and the precipitatedsolid was filtered and dried under vacuum to give2-(2,6-dimethyl-pyridin-4-yl)-7-fluoro-5-methoxy-3H-quinazolin-4-one asa light yellow solid. Yield: 0.28 g (37%).

To a solution of 2-methoxyethanol (3 mL) in dimethyl sulfoxide (8 mL),sodium hydride (60% suspension in mineral oil, 0.40 g, 9.40 mmol) wasadded in portions and the reaction mixture was stirred at roomtemperature for 1 hour. To this reaction mixture was added2-(2,6-dimethyl-pyridin-4-yl)-7-fluoro-5-methoxy-3H-quinazolin-4-one(0.28 g, 0.94 mmol) and the reaction mixture was stirred at 90° C. for16 hours. Water was added, acidified to pH approximately 4-5 with aceticacid, and the precipitated solid was filtered to give crude product,which was purified by preparative HPLC, to obtain the title compound asa white solid. Yield: 0.12 g (36%). MP 228.8-230.4° C. MS (ES) m/z:356.05 (M⁺+1). ¹H NMR (400 MHz, CDCl₃): δ 10.45 (s, 1H), 7.65 (s, 2H),6.85 (d, J=1.6 Hz, 1H), 6.61 (d, J=1.6 Hz, 1H), 4.27 (t, J=4.8 Hz, 2H),3.97 (s, 3H), 3.82 (t, J=4.8 Hz, 2H), 3.49 (s, 3H), 2.66 (s, 6H).

Example 106. Preparation of2-(2,6-Dimethylpyridin-4-yl)-5,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one

To a suspension of 2,6-dimethyl-pyridin-4-yl)-methanol (1.00 g, 7.30mmol) in acetonitrile (20 mL),1,2-benziodexol-3(1H)-one-1-hydroxy-1-oxide (IBX) (2.00 g, 7.30 mmol)was added and the reaction mixture was refluxed for 6 hours. The solidwas filtered off and washed with acetonitrile. The filtrate wasevaporated in vacuo, to give 2,6-dimethyl-pyridine-4-carbaldehyde as abrown liquid. Yield: 0.81 g (82%).

To a stirred solution of 2-amino-4,6-difluoro-benzamide (1.03 g, 6.00mmol) and 2,6-dimethyl-pyridine-4-carbaldehyde (0.81 g, 6.00 mmol) inN,N-dimethyl acetamide (15 mL), sodium hydrogen sulfite (58.5 wt %, 1.31g, 7.20 mmol) and p-toluenesulfonic acid monohydrate (0.11 g, 0.60 mmol)were added and the reaction mixture was stirred at 115° C. for 16 hours.The solvent was evaporated in vacuo, water was added, and theprecipitated solid was filtered to give2-(2,6-dimethyl-pyridin-4-yl)-5,7-difluoro-3H-quinazolin-4-one as ayellow solid, which was used in the next step without furtherpurification. Yield: 0.72 g (42%).

To a suspension of2-(2,6-dimethyl-pyridin-4-yl)-5,7-difluoro-3H-quinazolin-4-one (0.72 g,2.51 mmol) in DMF (10 mL), a solution of sodium methoxide in methanol(25 wt %, 1.36 g, 25.1 mmol) was added and the reaction mixture wasstirred at room temperature for 16 hours. Water was added, the mixturewas acidified to pH approximately 4-5 with acetic acid, and theprecipitated solid was filtered and dried under vacuum, to give2-(2,6-dimethyl-pyridin-4-yl)-7-fluoro-5-methoxy-3H-quinazolin-4-one asa light yellow solid. Yield: 0.28 g (37%).

To a solution of 2-methoxyethanol (3 mL) in dimethyl sulfoxide (8 mL),sodium hydride (60% suspension in mineral oil, 0.40 g, 9.40 mmol) wasadded in portions and the reaction mixture was stirred at roomtemperature for 1 hour. To this reaction mixture was added2-(2,6-dimethyl-pyridin-4-yl)-7-fluoro-5-methoxy-3H-quinazolin-4-one(0.28 g, 0.94 mmol); the reaction mixture was stirred at 90° C. for 16hours. Water was added, the mixture was acidified to pH approximately4-5 with acetic acid, and the precipitated solid was filtered, to givecrude product, which was purified by preparative HPLC to obtain thetitle compound. Yield: 0.03 g (8%). MP 149.8-151.4° C. MS (ES) m/z:400.13 (M⁺+1). ¹H NMR (400 MHz, CDCl₃): δ 7.54 (s, 2H), 6.85 (s, 1H),6.61 (s, 1H), 4.24 (m, 4H), 3.87 (t, J=5.2 Hz, 2H), 3.81 (t, J=5.2 Hz,2H), 3.49 (br s, 6H), 2.65 (s, 6H).

Example 107. Preparation of2-(2,6-Dimethylpyridin-4-yl)-7-methoxy-5-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-4(3H)-one

To a solution of 2,6-dimethyl-pyridine-4-carbaldehyde (0.99 g, 7.32mmol) and 2-amino-4,6-difluorobenzamide (1.26 g, 7.32 mmol) inN,N-dimethyl acetamide (20 mL) were added sodium hydrogen sulfite (58.5wt %, 1.59 g, 8.78 mmol) and p-toluenesulfonic acid (0.21 g, 1.09 mmol).The reaction mixture was stirred at 115° C. for 16 hours under nitrogen.After cooling to room temperature, the solvent was evaporated underreduced pressure. Water (50 mL) was added, the precipitated solid wasfiltered, washed with water, and dried under vacuum, to give2-(2,6-dimethyl-pyridin-4-yl)-5,7-difluoro-3H-quinazolin-4-one as ayellow solid. Yield: 0.63 g (30%).

To a solution of 2-pyrrolidin-1-yl-ethanol (5.09 g, 44.2 mmol) in DMF(10 mL) was added sodium hydride (60% suspension in mineral oil, 0.88 g,22.1 mmol) in small portions and the reaction mixture was stirred atroom temperature for 30 minutes. To this mixture was added2-(2,6-dimethyl-pyridin-4-yl)-5,7-difluoro-3H-quinazolin-4-one 0.63 g,2.21 mmol) and the reaction mixture was stirred at room temperature for16 hours. Water (20 mL) was added, and the mixture was neutralized, topH approximately 6 with acetic acid. Solvent was evaporated, and theresidue was dissolved in ethyl acetate, washed with water, and driedover anhydrous sodium sulfate, and concentrated in vacuo. The crudecompound was purified by the Simpliflash system (0-4% methanol in CH₂Cl₂as eluent) to give2-(2,6-dimethyl-pyridin-4-yl)-7-fluoro-5-(2-pyrrolidin-1-yl-ethoxy)-3H-quinazolin-4-oneas a yellow solid. Yield: 0.61 g (72%).

To a solution of2-(2,6-dimethyl-pyridin-4-yl)-7-fluoro-5-(2-pyrrolidin-1-yl-ethoxy)-3H-quinazolin-4-one(0.30 g, 0.80 mmol) in anhydrous DMF (5 mL) was added a solution ofsodium methoxide in methanol (25 wt %, 0.43 g, 8.00 mmol) and thereaction mixture was stirred at 70° C. for 16 h. After cooling to roomtemperature, water (10 mL) was added, and the mixture was neutralized topH approximately 6 with acetic acid. The solvent was evaporated, and theresidue was purified by the Simpliflash system (2% methanol in CH₂Cl₂and then 4% 7.0 M ammonia in methanol and CH₂Cl₂ as eluent) to give thetitle compound as a yellow solid. Yield: 0.100 g (32%). MP 190-191° C.¹H NMR (400 MHz, CDCl₃): δ 7.59 (s, 2H), 6.86 (d, J=1.95 Hz, 1H), 6.53(d, J=1.95 Hz, 1H), 4.25 (t, J=6.05 Hz, 2H), 3.93 (s, 3H), 3.03 (t,J=6.24 Hz, 2H), 2.69 (br s, 4H), 2.64 (s, 6H), 1.93-1.70 (m, 4H). MS(ES⁺) m/z: 395.22 (M+1) and 298.12 (100%).

Example 108. Preparation of2-(2,6-Dimethylpyridin-4-yl)-6-((4-methylpiperazin-1-yl)methyl)quinazolin-4(3H)-one

To a mixture of 5-methyl-2-nitrobenzoic acid (45.0 g, 0.248 mol) andpotassium carbonate (138.2 g, 1.0 mol) in acetonitrile (700 mL), methyliodide (78 mL, 1.25 mol) was added. The reaction mixture was stirred atroom temperature for 12 hours, then the solution was filtered. Thefiltrate was concentrated under reduced pressure. The resulting solidwas dissolved in ethyl acetate and washed with water and brine. Thecrude 5-methyl-2-nitrobenzoic acid methyl ester was used in the nextstep without further purification. Yield: 27.1 g (56%).

5-Methyl-2-nitrobenzoic acid methyl ester (27.1 g, 138.8 mmol) wasdissolved in carbon tetrachloride (500 mL), and N-bromosuccinimide (29.6g, 166.6 mmol) was added, followed by benzoyl peroxide (6.72 g, 27.7mmol). The mixture was illuminated and gently refluxed for 4 hours.Then, the mixture was cooled and concentrated, then purified by columnchromatography silica gel 230-400 mesh; 10% ethyl acetate in hexanes aseluent) to give 5-bromomethyl-2-nitrobenzoic acid methyl ester. Yield:17.9 g (47%).

To a solution of 5-bromomethyl-2-nitrobenzoic acid methyl ester (3.00 g,10.9 mmol) in CH₂Cl₂ (100 mL) was added triethylamine (3.30 g, 33.0mmol) and 1-methylpiperazine (3.30 g, 33.0 mmol). The mixture was heatedat 50° C. under nitrogen for 16 hours, then concentrated to give crude5-(4-methylpiperazin-1-ylmethyl)-2-nitrobenzoic acid methyl ester, whichwas purified by column chromatography (silica gel 230-400 mesh; 1-5%methanol in dichloromethane as eluent). Yield: 3.0 g (93%). It wasfurther converted to its hydrochloride salt (3.7 g) by stirring in 1 MHCl in ether and was isolated by filtration.

To a solution of 5-(4-methylpiperazin-1-ylmethyl)-2-nitrobenzoic acidmethyl ester hydrochloride salt (3.70 g, 10.0 mmol) in acetic acid (50mL) was added iron powder (1.80 g, 32.1 mmol), and the mixture wasstirred at 70° C. for 2 hours; TLC indicated completion of the reaction.The mixture was cooled and concentrated; the residue was taken in 7 Nammonia in methanol (50 mL) and filtered. The filtrate was evaporated todryness and purified by column chromatography (silica gel 230-400 mesh;5-10% methanol in dichloromethane as eluent). Yield: 4.3 g (crude). Thecrude 2-amino-5-(4-methyl-piperazin-1-ylmethyl)benzoic acid methyl esterwas used in the next step without further purification.

To a suspension of 2-amino-5-(4-methyl-piperazin-1-ylmethyl)benzoic acidmethyl ester (4.30 g, 10.0 mmol) in water (30 mL) and methanol (10 mL)was added lithium hydroxide (1.26 g, 30.0 mmol); the mixture was stirredat room temperature for 12 hours. An additional amount of lithiumhydroxide (0.6 g, 15.0 mmol) was added, and heated at 40° C. for 15hours; TLC indicated completion of the reaction. The mixture was cooled,concentrated, the residue was adjusted to pH ˜5 with 6 N HCl, andevaporated to dryness, to provide crude2-amino-5-(4-methyl-piperazin-1-ylmethyl)benzoic acid. Yield: 6.2 g,along with inorganic salt. It was used in the next step without furtherpurification.

To a suspension of 2-amino-5-(4-methyl-piperazin-1-ylmethyl)benzoic acid(crude 1.28 g, 3.00 mmol) in THF (18 mL) and DMF (7 mL), EDCI (0.77 g,4.00 mmol), and HOBT (0.50 g, 3.30 mmol) were added and stirred at roomtemperature for 20 minutes. Then, N-methylmorpholine (0.33 g, 3.30 mmol)and NH₄OH (aq. 50% v/v, 3.50 mL, 50.0 mmol) were added. The mixture wasstirred at room temperature for 48 hours. The solvent was evaporated,the residue was purified by column chromatography (silica gel 230-400mesh; 5-10% 2 M ammonia in methanol and dichloromethane as eluent) togive 2-amino-5-(4-methyl-piperazin-1-ylmethyl)benzamide as a whitesolid. Yield: 0.416 g (55% for two steps).

To a solution of 2,6-dimethylpyridine-4-carbaldehyde (0.14 g, 1.00 mmol)in N,N-dimethyl acetamide (8 mL) were added2-amino-5-(4-methyl-piperazin-1-ylmethyl)benzamide (0.25 g, 1.00 mmol),sodium hydrogensulfite (0.18 g, 110 mmol), and p-toluenesulfonic acid(0.057 g, 0.30 mmol). The reaction mixture was stirred at 115° C. for 20hours under nitrogen, then cooled to room temperature. Solvent wasevaporated under reduced pressure. The residue was dissolved indichloromethane, washed with sat. NaHCO₃, water, then brine, and driedover anhydrous sodium sulfate. Solvent was evaporated and the residuewas purified by column chromatography (silica gel 230-400 mesh; 2-3% 7 Mammonia in methanol and dichloromethane as eluent) to give the titlecompound. Yield: 0.035 g (9.6%). MP 229-230° C. ¹H NMR (400 MHz, CDCl₃):δ 8.30 (br s, 1H), 7.88 (s, 2H), 7.84 (m, 2H), 3.66 (s, 2H), 2.72 (s,6H), 2.50 (br s, 8H), 2.30 (s, 3H). MS (ES) m/z: 364.17 (M+1), 182.67(100%).

Example 109. Preparation of2-(2,6-Dimethylpyridin-4-yl)-5-methoxy-7-(2-phenoxyethoxy)quinazolin-4(3H)-one

To a solution of 2-phenoxy-ethanol (0.90 g, 6.50 mmol) in DMSO (5 mL)was added sodium hydride (60% in mineral oil, 0.16 g, 4.00 mmol) insmall portions. The reaction mixture was stirred at room temperatureunder nitrogen for 1 hour.2-(2,6-Dimethyl-pyridin-4-yl)-7-fluoro-5-methoxy-3H-quinazolin-4-one(0.20 g, 0.67 mmol) was added and stirring continued at 90° C. for 17hours. The reaction was then cooled to room temperature, water (100 mL)was added, and was extracted with ethyl acetate (200 mL). The organicphase was washed with brine and dried over anhydrous Na₂SO₄. Solvent wasremoved and the crude compound was purified by column chromatography(silica gel 230-400 mesh; 5% methanol in CH₂Cl₂ as eluent) to give thetitle compound as a white solid. Yield: 70 mg (25%). MP 223-224° C. ¹HNMR (400 MHz, CDCl₃): δ 11.35 (s, 1H), 7.75 (s, 2H), 7.32 (t, J=8.0 Hz,2H), 7.02-6.97 (m, 3H), 6.91 (d, J=2.0 Hz, 1H), 6.60 (d, J=1.6 Hz, 1H),4.49-4.47 (m, 2H), 4.41-4.39 (m, 2H), 3.97 (s, 3H), 2.67 (s, 6H). MS(ES⁺) m/z: 418.08 (M+1).

Example 110. Preparation of2-(2,6-Dimethylpyridin-4-yl)-7-methoxy-5-(2-phenoxyethoxy)quinazolin-4(3H)-one

A solution of 2,6-lutidine N-oxide (41.6 g, 0.337 mol, 1.0 equiv.) indry DCM (650 mL) was added to a flask containing trimethyloxoniumtetrafluoroborate (50.0 g, 0.337 mol, 1.0 equiv.) at room temperature.under a nitrogen atmosphere. The mixture was stirred at room temperaturefor 3.0 hours, then concentrated in vacuo to give 78 g of crude4-hydroxymethyl-2,6-dimethylpyridine. The crude product was dissolved inmethanol (500 mL) and the solution was heated to reflux under a nitrogenatmosphere, then a solution of ammonium persulfate (24.6 g, 0.101 mol)in water (100 mL) was added dropwise. The mixture was stirred at refluxfor 16 hours; TLC indicated complete reaction. Half of the solvents wereremoved in vacuo, then quenched with 10% NaOH solution to pHapproximately 7, and evaporated to dryness. The residue was dissolved inmethanol and filtered, the filtrate was concentrated in vacuum, andpurified by column chromatographt (eluting with methanol:DCM=5-15%) togive the title compound as a white solid. Yield: 24.7 g (52%).

4-Hydroxymethyl-2,6-dimethylpyridine (24.7 g, 180 mmol, 1.0 equiv.) wasdissolved in DMSO (200 mL), and IBX (53.0 g, 189 mmol, 1.05 equiv.) wasadded in portions, the mixture was stirred at room temperature for 2hours; TLC indicated complete reaction. The mixture was filtered, washedwith water and ether. The filtrate was extracted with ether (4×150 mL);the combined extracts were washed with water and brine, dried overanhydrous sodium sulfate, and concentrated to give the crude product,which was purified by column chromatography (20% ether in hexanes aseluent) to give 2,6-dimethyl4-pyridinecarboxaldehyde as a yellow oil.Yield: 20.0 g (82%).

To a solution of 2,6-dimethyl-pyridine-4-carbaldehyde (5.0 g, 36.5 mmol)and 2-amino-4,6-difluorobenzamide (6.28 g, 36.5 mmol) in N,N-dimethylacetamide (80 mL) were added sodium hydrogen sulfite (7.95 g, 43.8 mmol)and p-toluenesulfonic acid (0.7 g, 3.65 mmol). The reaction mixture wasstirred at 115° C. for 16 hours under nitrogen. The reaction mixture wascooled to room temperature, diluted with water, the precipitate wascollected by filtration, washed with sat. NaHCO₃ and brine, and dried invacuo to give2-(2,6-dimethylpyridin-4-yl)-5,7-difluoro-3H-quinazolin-4-one as a whitesolid. Yield: 2.82 g (26.8%).

To a solution of 2-phenoxyethanol (4.81 g, 34.8 mmol) in DMF (20 mL) wasadded sodium hydride (60% suspension in mineral oil, 0.70 g, 17.4 mmol)in portions and the reaction mixture was stirred at room temperature for1 hour. To this mixture was added2-(2,6-dimethylpyridin-4-yl)-5,7-difluoro-3H-quinazolin-4-one (0.50 g,1.74 mmol) and the reaction mixture was stirred at room temperature for16 hours. Water (1 mL) was added, neutralized to pH approximately 6-7with acetic acid, concentrated, dissolved in ethyl acetate, washed withwater, dried over anhydrous sodium sulfate, and concentrated in vacuo.The residue was purified by column chromatography (eluted with 50% ethylacetate in hexanes, then 5% methanol in DCM) to give2-(2,6-dimethylpyridin-4-yl)-7-fluoro-5-(2-phenoxyethoxy)-3H-quinazolin-4-oneas a light yellow solid. Yield: 0.59 g (83%).

To a suspension of2-(2,6-dimethylpyridin-4-yl)-7-fluoro-5-(2-phenoxyethoxy)-3H-quinazolin-4-one(0.59 g, 1.45 mmol) in DMF (10 mL) was added a solution of sodiummethoxide in methanol (25 wt %, 3.15 g, 14.5 mmol) and the reactionmixture was stirred at approximately 70-80° C. for 48 hours, then cooledto room temperature. Water (1 mL) was added, the mixture was neutralizedto pH approximately 6-7 with acetic acid, concentrated, dissolved inDCM, washed with water and brine, dried over anhydrous sodium sulfate,concentrated in vacuo, and the residue was passed through a column(eluted with 2% methanol in DCM), to give 0.12 g of the desired product.The crude product was washed with acetonitrile, then solubilized indioxane, and precipitated by adding water to afford the title compoundas a white solid. Yield: 70 mg (11%). ¹H NMR (400 MHz, DMSO-d₆): δ 12.08(br s, 1H), 7.77 (s, 2H), 7.31 (t, J=7.81 Hz, 2H), 7.04 (d, J=8.20 Hz,2H), 6.96 (t, J=7.42 Hz, 1H), 6.83 (d, J=1.56 Hz, 1H), 6.69 (s, 1H),4.40-4.53 (m, 2H), 3.90 (s, 3H), 3.33 (s, 6H). MS (ES⁺) m/z: 418.14(M+1)⁺; MP 172.3-173.2° C.

Example 111. Preparation of2-(2,6-Dimethylpyridin-4-yl)-7-methoxy-5-(2-methoxyethoxy)quinazolin-4(3H)-one

To a solution of 2-methoxyethanol (2.65 g, 34.8 mmol) in DMF (38 mL) wasadded sodium hydride (60% suspension in mineral oil, 0.70 g, 17.4 mmol)in portions and the reaction mixture was stirred at room temperature for0.5 hours. To this mixture was added2-(2,6-dimethylpyridin-4-yl)-5,7-difluoro-3H-quinazolin-4-one (0.50 g,1.74 mmol) and the reaction mixture was stirred at room temperature for16 hours. Water (1.5 mL) was added, the mixture was neutralized to pHapproximately 6-7 with acetic acid, concentrated, dissolved in ethylacetate (200 mL), washed with water and brine, dried over anhydroussodium sulfate, and concentrated in vacuo. The residue was washed withhexanes to give2-(2,6-dimethylpyridin-4-yl)-7-fluoro-5-(2-methoxyethoxy)-3H-quinazolin-4-one)as a pale solid. Yield: 0.52 g (87%).

To a suspension of2-(2,6-dimethylpyridin-4-yl)-7-fluoro-5-(2-methoxyethoxy)-3H-quinazolin-4-one(0.42 g, 1.22 mmol) in DMF (10 mL) was added a solution of sodiummethoxide in methanol (25 wt %, 2.8 g, 12.8 mmol) and the reactionmixture was stirred at 70° C. for 16 hours, then cooled to roomtemperature. Water (1 mL) was added, the mixture was neutralized to pHapproximately 6 with acetic acid, diluted with water (50 mL), andextracted with ethyl acetate. The combined extracts were washed withwater and brine, dried over anhydrous sodium sulfate, and concentratedin vacuo, to give 0.30 g of crude compound. Further purification bycrystallization in acetone:Et₂O (1:3) gave the title compound as a whitesolid. Yield: 91 mg (15%). ¹H NMR (400 MHz, CDCl₃): δ 10.08 (br s, 1H),7.60 (br s, 2H), 6.87 (d, J=1.95 Hz, 2H), 6.55 (d, J=1.95 Hz, 2H), 4.25(t, J=4.88 Hz, 2H), 3.93 (s, 3H), 3.83 (d, J=4.29 Hz, 2H), 3.44 (s, 3H),2.64 (s, 6H). MS (ES⁺) m/z: 356.11 (M+1)⁺

Example 112. Preparation of2-(2,6-Dimethylpyridin-4-yl)-5-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-4(3H)-one

To a suspension of 2,6-dimethyl-pyridin-4-yl)-methanol (6.00 g, 0.043mol) in acetonitrile (150 mL),1,2-benziodexol-3(1H)-one-1-hydroxy-1-oxide (IBX) (14.8 g, 0.0503 mol)was added and the reaction mixture was refluxed for 2 hours. The solidwas filtered off and washed with acetonitrile. The filtrate wasevaporated in vacuo to give 2,6-dimethyl-pyridine-4-carbaldehyde as abrown liquid. Yield: 4.30 g (72.7%).

To a stirred solution of 2-amino-4,6-difluoro-benzamide (4.00 g, 0.0237mol) and 2,6-dimethyl-pyridine-4-carbaldehyde (3.20 g, 0.0237 mol) inN,N-dimethyl acetamide (15 mL), sodium hydrogen sulfite (58.5 wt %, 5.05g, 0.0284 mol) and p-toluenesulfonic acid monohydrate (0.90 g, 4.74mmol) were added and the reaction mixture was stirred at 130° C. for 16hours. The solvent was evaporated in vacuo, water was added, and theprecipitated solid was filtered to give2-(2,6-dimethyl-pyridin-4-yl)-5,7-difluoro-3H-quinazolin-4-one as ayellow solid, which was used in the next step without furtherpurifications. Yield: 3.70 g (42%).

To a suspension of2-(2,6-dimethyl-pyridin-4-yl)-5,7-difluoro-3H-quinazolin-4-one (2.70 g,9.4 mmol) in DMF (15 mL), a solution of sodium methoxide in methanol (25wt %, 6.0 g, 28.2 mmol) was added and the reaction mixture was stirredat room temperature for 16 hours. Water was added, the mixture wasacidified to pH approximately 4-5 with acetic acid, and the precipitatedsolid was filtered and dried under vacuum to give crude2-(2,6-dimethyl-pyridin-4-yl)-7-fluoro-5-methoxy-3H-quinazolin-4-one(2.40 g), which was further purified by column chromatography (silicagel 230-400 mesh; eluting with 2% methanol solution in dichloromethane)to yield pure compound as a light yellow solid. Yield: 0.35 g (12.4%).

To a solution of 2-pyrrolidin-1-yl-ethanol (1.15 g, 10 mmol) in dimethylsulfoxide (4 mL), sodium hydride (60% suspension in mineral oil, 0.20 g,5.0 mmol) was added in portions and the reaction mixture was stirred atroom temperature for 20 minutes. To this reaction mixture was added2-(2,6-dimethyl-pyridin-4-yl)-7-fluoro-5-methoxy-3H-quinazolin-4-one(0.30 g, to mmol) and the reaction mixture was stirred at 75° C. for 16hours. The reaction mixture was loaded onto a column and purified bycolumn chromatography (silica gel 230-400 mesh; eluting with 5% 7.0 Mammonia in methanol solution in dichloromethane), to obtain the titlecompound as a white solid. Yield: 0.163 g (41.3%). MP 227-229° C. MS(ES) m/z: 395.15 (M⁺+1). ¹H NMR (400 MHz, CDCl₃): δ 7.78 (s, 2H), 6.87(d, J=2.4 Hz, 1H), 6.58 (d, J=2.4 Hz, 1H), 4.25 (t, J=6.0 Hz, 2H), 3.95(s, 3H), 2.97 (t, J=6.0 Hz, 2H), 2.66 (s, 6H), 2.63 (m, 4H), 1.83 (m,4H).

Example 113. Preparation of2-(2,6-Dimethylpyridin-4-yl)-7-(2-isopropoxyethoxy)-5-methoxyquinazolin-4(3H)-one

To a suspension of2-(2,6-dimethyl-pyridin-4-yl)-5,7-difluoro-3H-quinazolin-4-one (0.97 g,3.38 mmol) in anhydrous DMF (10 mL) was added a solution of sodiummethoxide in methanol (25 wt %, 1.09 g, 20.3 mmol). The reaction mixturebecame clear. The reaction mixture was stirred at room temperature for16 hours. Water (100 mL) was added, neutralized to pH approximately 6with aqueous 2N HCl. The separated solid was filtered, washed with water(50 mL), and dried under vacuum to give an off-white solid. Yield: 0.94g (93%).

To a suspension of sodium hydride (60% suspension in mineral oil, 0.24g, 6.00 mmol) in anhydrous DMSO (10 mL) was added 2-isopropoxy-ethanolat room temperature under nitrogen. The mixture was stirred for 20minutes at room temperature, then2-(2,6-dimethyl-pyridin-4-yl)-7-fluoro-5-methoxy-3H-quinazolin-4-one(0.30 g, 1.00 mmol) was added and the reaction mixture was stirred at80° C. for 16 hours, then cooled to room temperature. Water (50 mL) wasadded, and the mixture was extracted with a mixture of ethyl acetate andTHF (4:1, 200 mL). The organic phase was washed with brine and driedover anhydrous sodium sulfate. Solvent was evaporated, and the crudecompound was purified by the Simpliflash system (3:15:82 methanol, ethylacetate and dichloromethane as eluent) to give the title compound as awhite solid. Yield: 127 mg (33%). MP 188-189° C. ¹H NMR (400 MHz,CDCl₃): δ 11.14 (br s, 1H), 7.72 (s, 2H), 6.86 (d, J=2.34 Hz, 1H), 6.59(d, J=2.34 Hz, 1H), 4.35-4.15 (m, 2H), 3.97 (s, 3H), 3.89-3.79 (m, 2H),3.78-3.64 (m, 1H), 2.66 (s, 6H), 1.23 (d, J=5.85 Hz, 6H). MS (ES⁺) m/z:384.20 (100%).

Example 114. Preparation of2-(2,6-dimethylpyridin-4-yl)-5,7-bis(2-isopropoxyethoxy)quinazolin-4(3H)-one

The title compound was isolated using the process described for Example113 as a white solid. Yield: 124 mg (27%). MP 124-125° C. ¹H NMR (400MHz, CDCl₃): δ 10.04 (br s, 1H), 7.60 (s, 2H), 6.85 (d, J=2.34 Hz, 1H),6.63 (d, J=2.34 Hz, 1H), 4.23 (t, J=4.88 Hz, 4H), 3.85 (dt, J=10.54 and5.27 Hz, 4H), 3.80-3.64 (m, 2H), 2.64 (s, 6H), 1.23 (d, J=6.24 Hz, 6H),1.17 (d, J=6.24 Hz, 6H). MS (ES⁺) m/z: 456.17 (100%).

Example 115. Preparation of7-(2-(Benzyloxy)ethoxy)-2-(2,6-dimethylpyridin-4-yl)-5-methoxyquinazolin-4(3H)-one

To a suspension of 2,6-dimethyl-pyridin-4-yl)-methanol (6.00 g, 0.043mol) in acetonitrile (150 mL),1,2-benziodexol-3(1H)-one-1-hydroxy-1-oxide (IBX) (14.8 g, 0.0503 mol)was added and the reaction mixture was refluxed for 2 hours. The solidwas filtered off and washed with acetonitrile. The filtrate wasevaporated in vacuo to give 2,6-dimethyl-pyridine-4-carbaldehyde as abrown liquid. Yield: 4.30 g (72.7%).

To a stirred solution of 2-amino-4,6-difluoro-benzamide (4.00 g, 0.0237mol) and 2,6-dimethyl-pyridine-4-carbaldehyde (3.20 g, 0.0237 mol) inN,N-dimethyl acetamide (15 mL), sodium hydrogen sulfite (58.5 wt %, 5.05g, 0.0284 mol), and p-toluene sulfonic acid monohydrate (0.90 g, 4.74mmol) were added and the reaction mixture was stirred at 130° C. for 16hours. The solvent was evaporated in vacuo, water was added, and theprecipitated solid was filtered to give2-(2,6-dimethyl-pyridin-4-yl)-5,7-difluoro-3H-quinazolin-4-one as ayellow solid, which was used in the next step without furtherpurification. Yield: 3.70 g (54.3%).

To a suspension of2-(2,6-dimethyl-pyridin-4-yl)-5,7-difluoro-3H-quinazolin-4-one (2.70 g,9.4 mmol) in DMF (15 mL), a solution of sodium methoxide in methanol (25wt %, 6.0 g, 28.2 mmol) was added and the reaction mixture was stirredat room temperature for 16 h. Water was added, acidified to pHapproximately 4-5 with acetic acid and the precipitated solid wasfiltered and dried under vacuum to give crude2-(2,6-dimethyl-pyridin-4-yl)-7-fluoro-5-methoxy-3H-quinazolin-4-one(2.40 g), which was further purified by column chromatography (silicagel 230-400 mesh; eluting with 2% methanol solution in dichloromethane)to yield pure compound as a light yellow solid. Yield: 0.35 g (12.4%).

To a solution of 2-benzyloxy-ethanol (1.15 g, 10.0 mmol) in dimethylsulfoxide (4 mL), sodium hydride (60% suspension in mineral oil, 0.20 g,5.0 mmol) was added in portions and the reaction mixture was stirred atroom temperature for 20 minutes. To this reaction mixture was added2-(2,6-dimethyl-pyridin-4-yl)-7-fluoro-5-methoxy-3H-quinazolin-4-one(0.30 g, 1.0 mmol) and the reaction mixture was stirred at 85° C. for 24hours. Water was added, and the mixture was acidified to pHapproximately 4-5 with acetic acid and the precipitated solid wasfiltered to give crude product, which was purified by columnchromatography (silica gel 230-400 mesh; eluting with hexane and ethylacetate 10:1) to obtain the title compound as a white solid. Yield:0.140 g (32.4%). MP 178-180° C. MS (ES) m/z: 432.18 (M⁺+1). ¹H NMR (400MHz, CDCl₃): δ 10.90 (s, 1H), 7.69 (s, 2H), 7.29-7.40 (m, 5H), 6.85 (d,J=2.0 Hz, 1H), 6.59 (d, J=2.0 Hz, 1H), 4.66 (s, 2H), 4.29 (m, 2H), 3.97(s, 3H), 3.89 (m, 2H), 2.66 (s, 6H).

Example 116. Preparation of2-(2,6-Dimethylpyridin-4-yl)-6-(2-morpholinoethyl)quinazolin-4(3H)-one

To a solution of 2-amino-5-(2-morpholin-4-yl-ethyl)-benzamide (0.18 g,0.70 mmol) in N,N-dimethyl acetamide (7 mL) under nitrogen atmospherewere added 2,6-dimethyl-pyridine-4-carbaldehyde (0.10 g, 0.70 mmol),sodium hydrogensulfite (58.5 wt %, 0.15 g, 1.40 mmol) andp-toluenesulfonic acid (0.34 g, 1.80 mmol). The resulting mixture washeated at 120° C. for 16 hours, then cooled to room temperature. Thesolvent was removed under reduced pressure, and the residue was dilutedwith methylene chloride (100 mL). The organic phase was washed withsaturated aqueous sodium bicarbonate solution, then water, and driedover anhydrous sodium sulfate. The crude orange solid (0.21 g) waspurified by column chromatography (silica gel 230-400 mesh; 95:5methylene chloride and MeOH as eluent) to give the title compound as ayellow solid. Yield: 0.11 g (42%). MP 248.5-249.3° C. ¹H NMR (400 MHz,CDCl₃): δ 11.6 (s, 1H), 8.18 (s, 1H), 7.87-7.76 (m, 3H), 7.76-7.65 (m,1H), 3.76 (t, J=4.49 Hz, 4H), 2.99 (t, J=8.01 Hz, 4H), 2.71 (s, 6H),2.75-2.65 (m, 2H), 2.56 (br s, 4H). MS (ES⁺) m/z: 363.16 (M+1).

Example 117. Preparation of2-(2-methylpyridin-4-yl)-6-(morpholinomethyl)quinazolin-4(3H)-one

A solution of n-butyllithium (1.6 M solution in hexanes, 6.32 mL, 12.6mmol) in THF (50 mL) was cooled to −78° C. A solution of4-bromo-2-methyl-pyridine (2.00 g, 11.6 mmol) in anhydrous THF (5 mL)was added. The resulting mixture was stirred for 5 minutes, thenanhydrous N,N dimethylformamide (3.39 g, 46.4 mmol) was added. Thesolution was stirred for 90 min at −78° C. and quenched with saturatedaqueous NH₄Cl solution (30 mL). The reaction mixture was warmed to roomtemperature. The mixture was extracted with ethyl acetate (3×100 mL),and the combined organic phase was washed with brine (100 mL) and driedover anyhdrous Na₂SO₄. The solvent was evaporated under reduced pressureto give 2-methyl-pyridine-4-carbaldehyde. Yield: 1.20 g, (85%).

To a solution of 2-amino-5-morpholin-4-ylmethyl-benzamide (0.58 g, 2.4mmol) and 2-methyl-pyridine-4-carbaldehyde (0.3 g, 2.4 mmol) inN,N-dimethylacetamide (10 mL) were added NaHSO₃ (58.5 wt %, 0.48 g, 2.7mmol) and p-TSA (0.23 g, 1.2 mmol) and the reaction mixture was heatedat 115° C. for 16 hours, and the solvent was removed under reducedpressure. The crude compound was purified by column chromatography(silica gel 230-400 mesh; eluting with 4% methanolic ammonia indichloromethane) to give the title compound as a white solid. Yield:0.18 g (22%). MP 267-268° C. ¹H NMR (400 MHz, DMSO-d₆): δ 11.74 (br s,1H), 8.77 (d, J=5.4 Hz, 1H), 8.29 (s, 1H), 8.07 (s, 1H), 7.94-7.83 (m,3H), 3.75 (t, J=4.2 Hz, 4H), 3.74 (s, 2H), 2.77 (s, 6H), 2.53-2.46 (m,4H). MS (ES⁺) m/z: 337.41 (M+1).

Example 118. Preparation of5-methoxy-7-(2-methoxyethoxy)-2-(2-methylpyridin-4-yl)quinazolin-4(3H)-one

To a solution of 2-amino-4,6-difluoro-benzamide (0.71 g, 4.10 mmol) and2-methyl-pyridine-4-carbaldehyde (0.50 g, 4.10 mmol) inN,N-dimethylacetamide (10 mL) were added NaHSO₃ (58.5 wt %, 1.00 g, 5.70mmol) and p-TSA (0.16. g, 0.08 mmol). The reaction mixture was heated at115° C. for 30 hours, then cooled to room temperature. The solvent wasremoved under reduced pressure. The crude compound was purified bycolumn chromatography (silica gel 230-400 mesh; 5% methanol indichloromethane) to afford5,7-difluoro-2-(2-methyl-pyridin-4-yl)-3H-quinazolin-4-one as a lightyellow solid. Yield: 0.30 g (26%).

To a suspension of5,7-difluoro-2-(2-methyl-pyridin-4-yl)-3H-quinazolin-4-one (0.30 g, 1.09mmol) in anhydrous DMF (8 mL) was added a solution of sodium methoxidein methanol (25 wt %, 0.59 g, 10.9 mmol) and the reaction mixture wasstirred at room temperature for 3 hours. Water was added, the mixturewas acidified to pH approximately 5 with acetic acid, and theprecipitated solid was filtered and dried under vacuum to give7-fluoro-5-methoxy-2-(2-methyl-pyridin-4-yl)-3H-quinazolin-4-one as alight yellow solid. Yield: 0.24 g (76%).

To a solution of 2-methoxy-ethanol (0.64 g, 8.40 mmol) in anhydrous DMSO(4 mL) was added sodium hydride (60% suspension in mineral oil, 0.12 g,5.00 mmol) in small portions and the reaction mixture was stirred atroom temperature for 30 minutes. To this mixture was added a solution of7-fluoro-5-methoxy-2-(2-methyl-pyridin-4-yl)-3H-quinazolin-4-one (0.24g, 0.84 mmol) in anhydrous DMSO (12 mL). The reaction mixture wasstirred at 80° C. for 3 hours, then cooled to room temperature, anddiluted with ether (500 mL). The solid was filtered and washed withether. The crude compound was purified by column chromatography (silicagel 230-400 mesh; 4% methanol in dichloromethane). The compound wasfurther purified by preparative HPLC to give the title compound as awhite solid. Yield: 60 mg (21%). MP 260-262° C. ¹H NMR (400 MHz,DMSO-d₅): δ 8.62 (d, J=5.07 Hz, 1H), 7.98 (s, 1H), 7.88 (d, J=5.07 Hz,1H), 6.80 (d, J=2.34 Hz, 1H), 6.61 (d, J=2.34 Hz, 1H), 4.25 (t, J=4.68Hz, 2H), 3.86 (s, 3H), 3.71 (t, J=3.90 Hz, 2H), 3.33 (s, 3H), 2.57 (s,3H). MS (ES) m/z: 342.07 (M+1) (100%).

Example 119. Preparation of2-(2,6-Dimethylpyridin-4-yl)-6-(2-(pyrrolidin-1-yl)ethyl)quinazolin-4(3H)-one

To a suspension of 1H-benzotriazole (10.0 g, 83.9 mmol) in water (84 mL)was added pyrrolidine 2 (6.3 mL, 226.6 mmol). After 10 minutes ofvigorous stirring at room temperature, formaldehyde 37% aqueous solutionwas added. The reaction mixture was stirred for 1 hour, then theprecipitate was filtered off, and washed with water to afford1-pyrrolidin-1-ylmethyl-1H-benzoimidazole as an off-white solid. Yield:14.58 g (85.9%).

To a mixture of zinc powder (1.05 g, 16.05 mmol) and1-pyrrolidin-1-ylmethyl-1H-benzoimidazole (2.95 g, 14.59 mmol) inN,N-dimethyl formamide (40 mL) under a nitrogen atmosphere was added5-bromomethyl-2-nitro-benzoic acid methyl ester (4.0 g, 14.59 mmol). Thereaction mixture was stirred at room temperature for 24 hours, thenquenched at 0° C. with an ice-cold 25% aqueous solution of ammoniumhydroxide (108 mL). The stirring was continued until most of the solidhad dissolved. Undissolved solid was filtered off and the filtrate wasextracted with diethyl ether. The combined organic layers were washedwith 1 N aqueous sodium hydroxide, then water, and were dried overanhydrous sodium sulfate and concentrated under high vacuum to give2-nitro-5-(2-pyrrolidin-1-yl-ethyl)-benzoic acid methyl ester as anorange oil. Yield: 1.3 g (32%). The crude material was used for the nextstep without further purification.

To a solution of 2-nitro-5-(2-pyrrolidin-1-yl-ethyl)-benzoic acid methylester in THF (16 mL) was added 10% palladium on charcoal (0.23 g). Theresulting reaction mixture was hydrogenated under 40 psi for 2 hours,then the catalyst was filtered off and the filtrate concentrated underhigh vacuum to give 2-amino-5-(2-pyrrolidin-1-yl-ethyl)-benzoic acidmethyl ester as a yellow oil. Yield: 1.04 g (89.6%). The crude materialwas used in the next step without further purification.

To a solution of 2-amino-5-(2-pyrrolidin-1-yl-ethyl)-benzoic acid methylester (1.04 g, 4.19 mmol) in a mixture of THF (8 mL) and methanol (5 mL)was added lithium hydroxide (0.36 g), followed by water (3 mL). Thereaction mixture was stirred at room temperature overnight, and thenrefluxed for 4 hours. After cooling to room temperature, the was solventconcentrated. The pH was adjusted to approximately 5 with 2 N aqueoushydrochloric acid and the residue was evaporated to dryness to give2-amino-5-(2-pyrrolidin-1-yl-ethyl)-benzoic acid as a chloride salt.Yield: 1.84 g. The crude material was used in the next step withoutfurther purification.

To a solution of 2-amino-5-(2-pyrrolidin-1-yl-ethyl)-benzoic acid (0.41g, 1.75 mmol) in a mixture of THF (5.1 mL) and N,N-dimethyl formamide(1.75 mL) was added EDCI (0.84 g, 4.37 mmol), followed by HOBt (0.71 mL,5.25 mmol). The reaction mixture was stirred for 30 minutes. Then,N-methyl morpholine (0.67 mL, 6.12 mmol) was added, followed by 50%aqueous ammonium hydroxide (1.2 mL, 17.5 mmol). The resulting mixturewas stirred at room temperature for 24 hours. Then, the solvent wasreduced and the residue was extracted with methylene chloride. Thecombined organic layers were washed with brine, water, and dried oversodium sulfate. After solvent evaporation under high vacuum, the crudeorange oil (0.72 g) was purified by column chromatography (silica gel230-400 mesh; 5/95 methylene chloride/7 N ammonia in MeOH as eluent) togive pure 2-amino-5-(2-pyrrolidin-1-yl-ethyl)-benzamide as a lightyellow viscous oil. Yield: 0.16 g (39.2%).

To a solution of 2-amino-5-(2-pyrrolidin-1-yl-ethyl)-benzamide (0.16 g,0.69 mmol) in N,N-dimethyl acetamide (7 mL) under a nitrogen atmospherewas added 2,6-dimethyl-pyridine-4-carbaldehyde (0.09 g, 0.68 mmol),followed by sodium hydrogensulfite (0.14 g, 1.36 mmol) andp-toluenesulfonic acid (0.32 g, 1.7 mmol). The resulting mixture washeated at 120° C. overnight. Then, the solvent was removed under reducedpressure, the residue was diluted with ethyl acetate, and was extractedwith water. The pH of the water layer was made basic by adding sodiumbicarbonate, then the layer was extracted with methylene chloride, driedover anhydroussodium sulfate, and was evaporated under high vacuum. Thecrude yellow solid (0.09 g) was purified by column chromatography(silica gel 230-400 mesh; 95/5 methylene chloride/MeOH as eluent) toafford the title compound as a yellow solid. Yield: 54 mg (23%). MP212.3-213.2° C. ¹H NMR (400 MHz, CDCl₃): δ 8.19 (s, 1H), 8.19 (br s,1H), 7.83-7.77 (m, 1H), 7.76-7.70 (m, 3H), 3.0-3.15 (m, 2H), 2.78-2.88(m, 2H), 2.7 (s, 6H), 2.58-2.68 (m, 4H), 1.8-1.95 (m, 4H). MS (ES⁺) m/z:347.11 (M+1).

Example 120. Preparation of2-(2,6-Dimethylpyridin-4-yl)-7-(2-methoxyethoxy)-5-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-4(3H)-one

To a solution of 2-pyrrolidin-1-yl-ethanol (5.09 g, 44.2 mmol) in DMF(10 mL) was added sodium hydride (60% suspension in mineral oil, 0.88 g,22.1 mmol) in small portions and the reaction mixture was stirred atroom temperature for 30 minutes. To this mixture was added2-(2,6-dimethyl-pyridin-4-yl)-5,7-difluoro-3H-quinazolin-4-one (0.63 g,2.21 mmol) and the reaction mixture was stirred at room temperature for16 hours. Water (20 mL) was added, and the mixture was neutralized to pHapproximately 6 with acetic acid. Solvent was evaporated, the residuewas dissolved in ethyl acetate, washed with water, dried over anhydroussodium sulfate, and concentrated in vacuo. Crude compound was purifiedby the Simpliflash system (0-4% methanol in CH₂Cl₂ as eluent) to afford2-(2,6-dimethyl-pyridin-4-yl)-7-fluoro-5-(2-pyrrolidin-1-yl-ethoxy)-3H-quinazolin-4-oneas a yellow solid. Yield: 0.61 g (72%).

To a solution of 2-methoxy-ethanol (1.35 g, 17.8 mmol) in DMF (10 mL)was added sodium hydride (60% suspension in mineral oil, 0.36 g, 8.89mmol) in small portions and the reaction mixture was stirred at roomtemperature for 30 minutes. To this mixture was added2-(2,6-dimethyl-pyridin-4-yl)-7-fluoro-5-(2-pyrrolidin-1-yl-ethoxy)-3H-quinazolin-4-one(0.34 g, 0.89 mmol) and the reaction mixture was stirred at 70-80° C.for 16 h, then cooled to room temperature. Water (10 mL) was added, andthe mixture was neutralized to pH approximately 6 with acetic acid.Solvent was evaporated; the residue was purified by the Simpliflashsystem (2-5% 7.0M ammonia in methanol and CH₂Cl₂ as eluent). Thecompound was further purified by preparative HPLC to give the titlecompound as a yellow solid. Yield: 72 mg (18%). MP 60.4-62.3° C. ¹H NMR(400 MHz, CDCl₃): δ 10.23 (br s, 1H), 8.50 (br s, 1H), 7.60 (s, 2H),6.76 (br s, 1H), 6.43 (br s, 1H), 4.35 (m, 2H), 4.21 (m, 2H), 3.79 (s,3H), 3.47-3.38 (m, 6H), 2.64 (s, 6H), 1.99 (m, 4H). MS (ES) m/z: 437.09(M−1) (100%).

Example 121. Preparation of2-(3-(2-Hydroxyethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one

To a suspension of sodium hydride (0.426 g, 10.7 mmol) in DMF (30 mL) atroom temperature was added 3-hydroxybenzaldehyde (1.00 g, 8.20 mmol).The resulting suspension was stirred at room temperature for 1 hour and(2-bromo-ethoxy)-tert-butyl-dimethyl-silane (4.4 mL, 20.5 mmol), wasthen added. The resulting mixture was stirred at 60° C. under nitrogenfor 14 hours, cooled to room temperature, diluted with water (100 mL),extracted with ethyl acetate (250 mL), and concentrated. The crudeproduct was purified by column chromatography (SiO₂, hexane/ethylacetate=4:1) to afford3-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-benzaldehyde. It wasre-dissolved in THF (50 mL), mixed with 1 N tetra-n-butylammoniumfluoride in THF (15 mL), and stirred at room temperature for 8 h. Thereaction mixture was then concentrated and the residue was purified bycolumn chromatography (SiO₂, hexane/ethyl acetate=4:1) to afford3-(2-hydroxy-ethoxy)-benzaldehyde as a colorless oil. Yield: 0.68 g (50%for two steps).

A mixture of 2-amino-4,6-dimethoxy-benzamide (195 mg, 1.00 mmol),3-(2-hydroxy-ethoxy)-benzaldehyde (166 mg, 1.00 mmol), p-toluenesulfonicacid monohydrate (38 mg, 0.20 mmol), and sodium bisulfite (264 mg, 1.50mmol) in N,N-dimethylacetamide (10 mL) was stirred at 130° C. undernitrogen for 14 hours, cooled to room temperature, and diluted with 0.2N potassium carbonate aqueous solution (50 mL). It was extracted withethyl acetate (250 mL), dried over sodium sulfate, and concentrated. Thesolid residue was re-dissolved in dichloromethane (5 mL), andprecipitated with ethyl acetate (15 mL) and hexanes (50 mL). It wasfiltered and washed with hexanes to afford the title compound as ayellow solid. Yield: 70 mg (20%). MP 244.8-246.0° C. ¹H NMR (400 MHz,CDCl₃): δ 7.64 (d, 1H), 7.60 (d, 1H), 7.45 (t, 1H), 7.12 (dd, 1H), 6.84(d, 1H), 6.48 (d, 1H), 4.21 (t, 2H), 4.03 (t, 2H), 3.99 (s, 3H), 3.94(s, 3H). MS (ES⁺) m/z: 343.55 (M+1).

Example 122. Preparation of2-(3-(2-Hydroxyethoxy)-5-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one

To a solution of 3,5-dimethyl-phenol (3.000 g, 24.55 mmol) inN,N-dimethylformamide (120 mL) under nitrogen were added potassiumcarbonate (16.96 g, 122.7 mmol) and(2-bromoethoxy)-tert-butyldimethylsilane (7.90 mL, 36.8 mmol). Theresulting slurry was heated at reflux for 20 hours; then, the solventwas removed under high vacuum. The residue was dissolved in ethylacetate and the solution was backwashed with 0.2 N aqueous sodiumhydroxide, water, and then brine, dried over sodium sulfate, andconcentrated. The crude material (5.69 g) was purified by columnchromatography (silica gel 230-400 mesh; methylene chloride as eluent)to give tert-butyl-[2-(3,5-dimethyl-phenoxy)-ethoxy]-dimethylsilane aslight yellow oil. Yield: 3.72 g (47%).

To a solution oftert-butyl-[2-(3,5-dimethyl-phenoxy)-ethoxy]-dimethylsilane (2.22 g,7.91 mmol) in carbon tetrachloride (50 mL) under nitrogen was addedN-bromosuccinimide (1.57 g, 8.70 mmol) and benzoyl peroxide (0.38 g,1.58 mmol). The resulting mixture was heated at reflux for 3 hours withsimultaneous illumination by a sun lamp. The precipitate was filteredoff and the filtrate was concentrated under reduced pressure. The crudematerial (3.99 g) was purified by column chromatography (silica gel230-400 mesh; 1/0 to 4/1 hexanes/EtOAc as eluent) to give[2-(3-bromomethyl-5-methyl-phenoxy)-ethoxy]-tert-butyl-dimethyl-silaneas a light yellow oil. Yield: 2.17 g (75%).

To a solution of[2-(3-bromomethyl-5-methyl-phenoxy)-ethoxy]-tert-butyl-dimethyl-silane(2.17 g, 6.04 mmol) under nitrogen in 2-nitopropane (2.0 mL, 20 mmol)was added sodium ethoxide (0.620 g, 9.06 mmol). The resulting mixturewas heated at 90° C. for 15 hours, and was then diluted with ethylacetate and quenched with saturated aqueous ammonium chloride. Theaqueous layer was extracted with ethyl acetate and the combined organiclayers were backwashed with water and brine, dried over sodium sulfate,and concentrated. The crude material (1.81 g) was purified by columnchromatography (silica gel 230-400 mesh; 1/0 to 4/1 hexanes/EtOAc aseluent) to give3-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-methyl-benzaldehyde as ayellow oil. Yield: 0.97 g (55%).

To a solution of 2-amino-4,6-dimethoxy-benzamide (0.350 g, 1.78 mmol) inN,N-dimethylacetamide (20 mL) under nitrogen was added3-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-methyl-benzaldehyde(0.520 g, 1.78 mmol) followed by sodium hydrogensulfite (0.270 g, 2.67mmol), and p-toluenesulfonic acid (0.033 g, 0.18 mmol). The resultingmixture was heated at 120° C. for 24 hours, then the solvent wasconcentrated to 5 mL under reduced pressure, and water was added toobtain a precipitate, which was filtered off and washed with Et₂O andmethylene chloride. The resulting solid was dissolved in hotCH₂Cl₂/MeOH, and then precipitated by adding Et₂O, and purified bypreparative thin-layer chromatography (DC-Fertigplatten SIL G-100 UV,9/1 methylene chloride/MeOH as eluent) to give the title compound as ayellow solid. Yield: 81 mg (13%). MP 106.9-109.1° C. ¹H NMR (400 MHz,CDCl₃): δ 7.86 (s, 1H), 7.41 (d, 2H), 6.82 (s, 1H), 6.57 (s, 1H),4.15-4.13 (m, 2H), 3.94-3.90 (m, 8H), 2.43 (s, 3H). MS (ES⁺) m/z: 357.53(M+1).

Example 123. Preparation of5,7-Dimethoxy-2-(3-methoxy-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-4(3H)-one

To a 1.0-L three-neck flask was added sodium ethanethiolate (80%, 28.5g, 271.0 mmol) and anhydrous DMF (225 mL). The mixture was heated to145° C. for 1.5 hours. Then, 3,5-dimethoxy-benzaldehyde (15.0 g, 90.0mmol) in anhydrous DMF (350 mL) was added over a period of 8 minutes.The reaction was kept at 145° C. for another 1 hour, then cooled to roomtemperature. Saturated sodium chloride solution (2.5 L) and formaline(37%, 240 mL) together with acetic acid (500 mL) was added. Theresulting solution was thoroughly extracted with ethyl acetate, theorganic phase was dried with sodium sulfate, and the solvent was removedunder vacuum. The crude compound was purified by column chromatography(silica gel 230-400 mesh; eluting with dichloromethane and ethyl acetate7:1) to give 3-hydroxy-5-methoxy-benzaldehyde as a white solid. Yield:12.0 g (88%).

3-Hydroxy-5-methoxy-benzaldehyde (12.0 g, 78.9 mmol) and[1,3]dioxolan-2-one (13.9 g, 157.0 mmol) in anhydrous DMF (50 mL) wasadded potassium carbonate (21.6 g, 157.0 mmol). The mixture was thenheated to 110° C. for 16 hours. The reaction mixture was cooled to roomtemperature. Solid potassium carbonate was filtered and washed withethyl acetate. The organic phase was collected and solvent was removed.The residue was purified by column chromatography (silica gel 230-400mesh; eluting with dichloromethane and ethyl acetate 7:1), to give3-(2-hydroxy-ethoxy)-5-methoxy-benzaldehyde as a brown liquid. Yield:10.0 g (65%).

To a solution of 2-amino-4,6-dimethoxy-benzamide (7.50 g, 38.2 mmol) and3-(2-hydroxy-ethoxy)-5-methoxy-benzaldehyde (7.50 g, 38.2 mmol) inN,N-dimethylacetamide (30 mL) was added NaHSO₃ (58.5 wt %, 4.37 g, 42.0mmol) and p-TSA (0.72 g, 3.8 mmol). The reaction mixture was heated to115-120° C. for 16 hours, and then cooled to room temperature.N,N-dimethylacetamide was removed under reduced pressure, the residuewas diluted with water (50 mL), and the solid was filtered, collected,and mixed with ether (50 mL), then filtered and dried under vacuum, togive2-[3-(2-hydroxy-ethoxy)-5-methoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-oneas a white solid. Yield: 10 g (70%).

To a solution of2-[3-(2-hydroxy-ethoxy)-5-methoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one(8.00 g, 21.5 mmol) in anhydrous DMF (30 mL) was added carbontetrabromide (9.80 g, 29.5 mmol) and triphenylphosphine (7.78 g, 29.5mmol). The reaction mixture was stirred at 40° C. for 7 hours. DMF wasremoved under vacuum and dichloromethane (200 mL) was added. The organicphase was washed with water (150 mL), brine (100 mL), and dried overanhydrous sodium sulfate. Solvent was removed and the residue was washedthree times with a mixture of ether and dichloromethane (20:1, 200 mL)to give2-[3-(2-bromo-ethoxy)-5-methoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one(5) as a white solid. Yield: 8.9 g (95%).

To a solution of2-[3-(2-bromo-ethoxy)-5-methoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one(7.10 g, 16.0 mmol) in THF (20 mL) was added pyrrolidine (11.38 g, 160.0mmol) and the reaction mixture was stirred at room temperature for 15hours. THF was removed under reduced pressure, the residue was purifiedby column chromatography (silica gel 230-400 mesh; eluting with 5% 2.0 Mammonia in methanol solution in dichloromethane) to give the titlecompound as a white solid. Yield: 3.2 g (47%). MP 159-160° C. ¹H NMR(400 MHz, CDCl₃): δ 10.66 (s, 1H), 7.25 (m, 2H), 6.84 (d, J=2.0 Hz, 1H),6.67 (t, J=2.4 Hz, 1H), 6.45 (d, J=2.0 Hz, 1H), 4.21 (t, J=6.0 Hz, 2H),3.95 (s, 3H), 3.93 (s, 3H), 3.89 (s, 3H), 2.93 (t, J=6.0 Hz, 2H), 2.64(m, 4H), 1.80 (m, 4H). MS (ES⁺) m/z: 426.20 (M+1).

Example 124. Preparation ofN-(2-(3-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-5-methoxyphenoxy)ethyl)acetamide

To a 1.0-L three-neck flask was added sodium ethanethiolate (80%, 28.5g, 271.0 mmol) and anhydrous DMF (225 mL). The mixture was heated to145° C. for 1.5 hours; then, a solution of 3,5-dimethoxy-benzaldehyde(15.0 g, 90.0 mmol) in anhydrous DMF (350 mL) was added over a period of8 minutes. The reaction was kept at 145° C. for 1 hour, then cooled toroom temperature. Saturated sodium chloride solution (2.5 L) andformaline (37%, 240 mL), together with acetic acid (500 mL), was added.The resulting solution was thoroughly extracted with ethyl acetate, andthe organic phase was dried over anhydrous sodium sulfate. Solvent wasremoved under vacuum, and the crude compound was purified by columnchromatography (silica gel 230-400 mesh; eluting with 7:1dichloromethane and ethyl acetate) to give3-hydroxy-5-methoxy-benzaldehyde as a white solid. Yield: 12.0 g (88%).

To a solution of 3-hydroxy-5-methoxy-benzaldehyde (12.0 g, 78.9 mmol) inanhydrous DMF (50 mL) was added [1,3]dioxolan-2-one (13.9 g, 157.0 mmol)and potassium carbonate (21.6 g, 157.0 mmol). The reaction mixture wasthen heated to 110° C. for 16 hours, then cooled to room temperature.Solid potassium carbonate was filtered and washed with ethyl acetate.The organic phase was collected and solvent was removed. The residue waspurified by column chromatography (silica gel 230-400 mesh; eluting with7:1 dichloromethane and ethyl acetate) to give3-(2-hydroxy-ethoxy)-5-methoxy-benzaldehyde as a brown liquid. Yield:10.0 g (65%).

To a solution of 2-amino-4,6-dimethoxy-benzamide (7.50 g, 38.2 mmol) and3-(2-hydroxy-ethoxy)-5-methoxy-benzaldehyde (7.50 g, 38.2 mmol) inN,N-dimethylacetamide (30 mL) were added NaHSO₃ (58.5 wt %, 4.37 g, 42.0mmol) and p-TSA (0.72 g, 3.8 mmol). The reaction mixture was heated to115-120° C. for 16 hours, and then cooled to room temperature.N,N-dimethylacetamide was removed under reduced pressure, the residuewas diluted with water (50 mL), and the solid was filtered, collectedand mixed with ether (50 mL), filtered, and dried under vacuum, to give2-[3-(2-hydroxy-ethoxy)-5-methoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-oneas a white solid. Yield: 10 g (70%).

To a solution of2-[3-(2-hydroxy-ethoxy)-5-methoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one(8.00 g, 21.5 mmol) in anhydrous DMF (30 mL) was added carbontetrabromide (9.80 g, 29.5 mmol) and triphenylphosphine (7.78 g, 29.5mmol). The reaction mixture was stirred at 40° C. for 7 hours. DMF wasremoved under vacuum and dichloromethane (200 mL) was added. The organicphase was washed with water (150 mL), then brine (100 mL), and driedover anhydrous sodium sulfate. Solvent was removed and the residue waswashed three times with a mixture of ether and dichloromethane (20:1,200 mL) to give2-[3-(2-bromo-ethoxy)-5-methoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-oneas a white solid. Yield: 8.9 g (95%).

To a solution of2-[3-(2-bromo-ethoxy)-5-methoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one(0.37 g, 0.84 mmol) in DMF (10 mL) was added sodium azide (0.14 g, 2.11mmol) and the reaction mixture was stirred at 70° C. for 7 hours. DMFwas removed under reduced pressure and dichloromethane (100 mL) wasadded. The organic phase was washed with water (50 mL), then brine (50mL), and dried over anhydrous sodium sulfate. Solvent was removed andthe residue was purified by column chromatography (silica gel 230-400mesh; 30-40% ethyl acetate in dichloromethane as eluent) to give a whitesolid. Yield: 0.23 g (69%).

2-[3-(2-Azido-ethoxy)-5-methoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one(90 mg, 0.22 mmol) was taken in thioacetic acid (2 mL) and the reactionmixture was stirred at room temperature for 2 hours. Thioacetic acid wasremoved under reduced pressure, and the residue was purified by columnchromatography (silica gel 230-400 mesh; 3.5% methanol indichloromethane as eluent) to give the title compound as a white solid.Yield: 45 mg (49%). MP 264-265° C. ¹H NMR (400 MHz, DMSO-d₆): δ 12.05(s, 1H), 8.13 (t, J=5.86 Hz, 1H), 7.39 (d, J=1.56 Hz, 2H), 6.76 (d,J=2.34 Hz, 1H), 6.69 (t, J=2.15 Hz, 1H), 6.55 (d, J=2.34 Hz, 1H), 4.07(t, J=5.67 Hz, 2H), 3.90 (s, 3H), 3.85 (s, 3H), 3.83 (s, 3H), 3.43 (q,J=5.47 Hz, 2H), 1.84 (s, 3H). MS (ES⁺) m/z: 414.11 (M+1).

Example 125. Preparation of2-(3,5-Dimethoxyphenyl)-6-(pyridin-4-ylamino)quinazolin-4(3H)-one

To a mixture of 2-amino-5-nitro-benzoic acid (12.9 g, 81.9 mmol),1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCI)(17.3 g, 90.1 mmol), 1-hydroxybenzotriazole hydrate (HOBt) (12.2 g, 90.1mmol) in THF (200 mL) was added 4-methylmorpholine (NMM) (9.91 mL, 90.1mmol). After 10 minutes, ammonium hydroxide (50% v/v, 50 mL) was added.The mixture was stirred at room temperature under nitrogen for 17 hours.Solvent was removed under reduced pressure. Water was added. The solidseparated was filtered, washed with aqueous NaHCO₃ solution, and withwater, and dried in air, to afford 2-amino-5-nitro-benzamide as a yellowsolid. Yield: 9.88 g (66%).

A mixture of 2-amino-5-nitro-benzamide (1.81 g, 10.0 mmol),3,5-dimethoxy-benzaldehyde (1.83 g, 11.0 mmol), sodium hydrogen sulfite(58.5 wt %, 3.94 g, 22.0 mmol), and p-toluenesulfonic acid monohydrate(0.38 g, 2.00 mmol) in N,N-dimethylacetamide (20 mL) was stirred at 150°C. for 17 hours under nitrogen and then cooled to room temperature.Saturated aqueous NaHCO₃ (approximately 1 mL) was added. The mixture wasstirred at room temperature for 2 hours, then concentrated to dryness.Water (80 mL) was added, stirred for 0.5 hours, and filtered. The solidwas air dried. The crude compound was purified by column chromatography(silica gel 230-400 mesh; ethyl acetate as eluent) to give6-amino-2-(3,5-dimethoxy-phenyl)-3H-quinazolin-4-one as a yellow solid.Yield: 1.50 g (50%).

6-Amino-2-(3,5-dimethoxy-phenyl)-3H-quinazolin-4-one (297 mg, 1.00mmol), 4-bromopyridine hydrochloride (194 mg, 1.00 mmol),tris(dibenzyldieneacetone)dipalladium(0) (18 mg, 0.02 mmol),1,1′-bis(diphenylphosphino)ferrocene (17 mg, 0.03 mmol), sodiumtert-butoxide (230 mg, 2.40 mmol) and pyridine (3 mL) were heated at140° C. in microwave oven (150 W) for 1 hour. The mixture wasconcentrated under vacuum to dryness. The residue was purified by columnchromatography (silica gel 230-400 mesh; 5% methanol in dichloromethaneand then 10% 2 N NH₃ in methanol and dichloromethane as eluent) to givethe title compound as a brown/beige solid. Yield: 176 mg (47%). MP289-290° C. ¹H NMR (400 MHz, DMSO-d₆): δ 9.24 (s, 1H), 8.29 (d, J=5.6Hz, 2H), 7.90 (s, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H),7.38 (s, 2H), 7.03 (d, J=5.2 Hz, 2H), 6.69 (s, 1H), 3.85 (s, 6H). MS(ES⁺) m/z: 375.13 (M+1).

Example 126. Preparation of5,7-Dimethoxy-2-(3-methoxyphenyl)quinazolin-4(3H)-one

A mixture of 2-amino-4,6-dimethoxybenzamide (0.0600 g, 0.306 mmol),3-methoxybenzaldehyde (0.306 mmol), NaHSO₃ (94%, 0.0474 g, 0.428 mmol),and p-TsOH.H₂O (0.0175 g, 0.0918 mmol) in DMA (3.06 mL) was heated at140° C. for 20 hours. The mixture was diluted with EtOAc (300 mL),washed with water (3×75 mL), then brine (75 mL), dried over sodiumsulfate, filtered, and concentrated under vacuum. The residue waspurified on silica gel (40 g, CH₂Cl₂/MeOH) and the product wasfreeze-dried from MeCN/H₂O to provide the title compound (69%) as anoff-white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 12.04 (s, 1H), 7.82-7.70(m, 2H), 7.43 (t, J=7.98 Hz, 1H), 7.13 (dd, J=8.19, 2.46 Hz, 1H), 6.76(d, J=2.19 Hz, 1H), 6.55 (d, J=2.19 Hz, 1H), 3.92-3.82 (m, 9H); MS(APCI) m/z 313 [C₁₇H₁₆N₂O₄+H]⁺.

Example 127. Quantification of hIL-6 mRNA

In this example, hIL-6 mRNA in tissue culture cells was quantitated tomeasure the transcriptional inhibition of hIL-6 when treated with acompound of the invention.

A human leukemic monocyte lymphoma cell line (U937) was plated (3.2×10⁵cells per well) in a 96-well plate in 100 μL RPMI-1640, anddifferentiated for 3 days prior to the addition of the compound ofinterest. The cells were pretreated for 1 h with the test compound priorto stimulation with lipolysaccharide from Escherichia coli. The cellswere incubated at 37° C. for 3 h before the cells were harvested. Attime of harvest, the spent media was removed from the cells and thecells were rinsed in 200 μL PBS. Cell lysis solution (70 μL) was addedthe cells in each well and incubated for 5-10 min at room temperature,to allow for complete cell lysis and detachment. mRNA was then preparedusing the “mRNA Catcher PLUS plate” (Invitrogen), according to theprotocol supplied. After the last wash, as much wash buffer as possiblewas aspirated without allowing the wells to dry. Elution buffer (E3, 70μL) was then added to each well. mRNA was then eluted by incubating themRNA Catcher PLUS plate with Elution Buffer for 5 min at 68° C. and thenimmediately placing the plate on ice.

The eluted mRNA isolated was then used in a one-step quantitativereal-time PCR reaction, using components of the Ultra Sense Kit togetherwith Applied Biosystems primer-probe mixes. Real-time PCR data wasanalyzed, normalizing the Ct values for hIL-6 to an internal control,prior to determining the fold induction of each unknown sample, relativeto the control.

In Table 2, an active compound is one that causes a ≥20% inhibition inIL-6 mRNA at a concentration less than or equal to 10 μM.

TABLE 2 Inhibition of IL-6 Example expression5,7-dimethoxy-2-(4-morpholinophenyl)quinazolin-4(3H)-one Active2-(4-((3R,5S)-4-acetyl-3,5-dimethylpiperazin-1-yl)phenyl)-5,7- Activedimethoxypyrido[2,3-d]pyrimidin-4(3H)-one2-(4-(4-hydroxypiperidin-1-yl)phenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-Active 4(3H)-one2-(4-((3R,5S)-4-acetyl-3,5-dimethylpiperazin-1-yl)phenyl)-5-methoxy-7-(2-Active methoxyethoxy)quinazolin-4(3H)-one2-(4-(4-isopropylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-oneActive2-(4-(4-acetylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-oneActive 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-oneActiveN-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-Active yl)acetamideN-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-Active yl)methanesulfonamide3-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-Active yl)-1,1-dimethylurea2-(4-(4-hexanoylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-oneActive2-(4-(4-isobutyrylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-oneActive2-(4-(4-benzoylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-oneActive2-(4-(4-(4-fluorobenzoyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-Active 4(3H)-oneN-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-Active yl)benzamide5,7-dimethoxy-2-(4-(4-picolinoylpiperazin-1-yl)phenyl)quinazolin-4(3H)-oneActive5,7-dimethoxy-2-(4-(4-nicotinoylpiperazin-1-yl)phenyl)quinazolin-4(3H)-oneActive2-(4-(4-isonicotinoylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-Active one 5,7-dimethoxy-2-(4-(4-(thiophene-2-carbonyl)piperazin-1-Active yl)phenyl)quinazolin-4(3H)-one2-(4-(4-(5-chloro-1-methyl-1H-pyrazole-4-carbonyl)piperazin-1-yl)phenyl)-Active 5,7-dimethoxyquinazolin-4(3H)-one5,7-dimethoxy-2-(4-(4-(3,3,3-trifluoropropanoyl)piperazin-1- Activeyl)phenyl)quinazolin-4(3H)-one2-(4-(4-(2,5-dichlorothiophene-3-carbonyl)piperazin-1-yl)phenyl)-5,7-Active dimethoxyquinazolin-4(3H)-one2-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)phenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one2-(4-(4-(4-fluorobenzyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-Active 4(3H)-one2-(4-(4-benzylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-oneActive2-(4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)phenyl)quinazolin-4(3H)-oneActive2-(4-(4-butylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-oneActive2-(4-(4-acetyl-1,4-diazepan-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-Active one2-(4-(1,4-diazepan-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one Active5,7-dimethoxy-2-(4-(4-methyl-1,4-diazepan-1-yl)phenyl)quinazolin-4(3H)-Active oneN-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-Active yl)-N-ethylacetamide2-(4-((3R,5S)-4-acetyl-3,5-dimethylpiperazin-1-yl)phenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one2-(4-((3R,5S)-3,5-dimethylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-Active 4(3H)-one2-(4-(4-acetyl-3-methylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-Active 4(3H)-oneN-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)pyrrolidin-Active 3-yl)acetamide2-(4-(4-isopropylpiperazin-1-yl)phenyl)-8-methoxyquinazolin-4(3H)-oneActive2-(4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-Active 4(3H)-oneN-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-Active yl)-N-isopropylacetamide5-chloro-2-(4-(4-isopropylpiperazin-1-yl)phenyl)quinazolin-4(3H)-oneActive 2-(4-((3R,5S)-4-isopropyl-3,5-dimethylpiperazin-1-yl)phenyl)-5,7-Active dimethoxyquinazolin-4(3H)-one5,7-dimethoxy-2-(4-(piperidin-4-yl)phenyl)quinazolin-4(3H)-one Active5,7-dimethoxy-2-(4-(3-(methylamino)pyrrolidin-1-yl)phenyl)quinazolin-4(3H)-Active one2-(4-((4-isopropylpiperazin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-Active 4(3H)-one2-(4-(4-(isopropylamino)piperidin-1-yl)phenyl)-5,7-dimethoxyquinazolin-Active 4(3H)-one2-(4-(1-acetylpiperidin-4-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-oneActive5,7-dimethoxy-2-(4-(3-methylpiperazin-1-yl)phenyl)quinazolin-4(3H)-oneActiveN-benzyl-N-(1-(5-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-Active yl)piperidin-4-yl)acetamide2-(6-(4-(benzylamino)piperidin-1-yl)pyridin-3-yl)-5,7-dimethoxyquinazolin-Active 4(3H)-one4-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperazine-1-Active carbaldehyde5,7-dimethoxy-2-(4-(4-oxopiperidin-1-yl)phenyl)pyrido[2,3-d]pyrimidin-Active 4(3H)-one tert-butyl4-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Activeyl)phenyl)piperidine-1-carboxylate2-(4-(dimethylamino)naphthalen-1-yl)-6,7-dimethoxyquinazolin-4(3H)-oneActive 2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxypyrido[2,3-Active d]pyrimidin-4(3H)-one2-(2-(hydroxymethyl)-1H-indol-5-yl)-5,7-dimethoxyquinazolin-4(3H)-oneActive2-(2-(2-hydroxyethyl)-1H-indol-5-yl)-5,7-dimethoxyquinazolin-4(3H)-oneActive5,7-dimethoxy-2-(2-(pyrrolidin-1-ylmethyl)-1H-indol-5-yl)quinazolin-4(3H)-Active one2-(3-(hydroxymethyl)-1H-indazol-5-yl)-5,7-dimethoxyquinazolin-4(3H)-oneActive5,7-dimethoxy-2-(2-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-5-yl)quinazolin-4(3H)-Active one2-(2-((dimethylamino)methyl)-1H-indol-5-yl)-5,7-dimethoxyquinazolin-4(3H)-Active one N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Activeyl)phenyl)methanesulfonamide5,7-dimethoxy-2-(4-(pyridin-4-ylamino)phenyl)quinazolin-4(3H)-one Active5,7-dimethoxy-2-(4-(p-tolylamino)phenyl)quinazolin-4(3H)-one Active5,7-dimethoxy-2-(4-(pyridin-3-ylamino)phenyl)quinazolin-4(3H)-one Active3-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-6,8-dimethoxyisoquinolin-Active 1(2H)-one2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-5,7-dimethoxyquinazolin-Active 4(3H)-one3-(3,5-dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6,8- Activedimethoxyisoquinolin-1(2H)-one2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)quinazolin-4(3H)-one Active7-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-2,4-dimethoxy-1,6- Activenaphthyridin-5(6H)-one5,7-dimethoxy-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)quinazolin-Active 4(3H)-one5,7-dimethoxy-2-(4-(morpholinomethyl)phenyl)quinazolin-4(3H)-one Active2-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-Active one 2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-Active dimethoxyquinazolin-4(3H)-one4-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)-N,N-Active dimethylpiperidine-1-carboxamide2-(4-(1-acetylpiperidin-4-yloxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-oneActive 2-(4-(2-(isoindolin-2-yl)ethoxy)-3,5-dimethylphenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-methoxyquinazolin-Active 4(3H)-one5,7-dichloro-2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-Active 4(3H)-one2-(3,5-dimethyl-4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-5,7-dimethoxy-3-(3-Active (pyrrolidin-1-yl)propyl)quinazolin-4(3H)-one2-(4-(2-(4-acetylpiperazin-1-yl)ethoxy)-3,5-dimethylphenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one2-(4-(2-(1H-imidazol-1-yl)ethoxy)-3,5-dimethylphenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-7-methoxyquinazolin-Active 4(3H)-one2-(3,5-dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one2-(3,5-dimethyl-4-(2-(piperidin-1-yl)ethoxy)phenyl)-5,7-dimethoxyquinazolin-Active 4(3H)-one5,7-dimethoxy-2-(3-methyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-Active 4(3H)-one3-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6- Activedimethylphenoxy)ethyl)-1-isopropylimidazolidine-2,4-dione2-(3,5-dimethyl-4-(3-(pyrrolidin-1-yl)propoxy)phenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one5,7-dimethoxy-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-4(3H)-oneActive2-(3,5-dimethyl-4-(3-(pyrrolidin-1-yl)propyl)phenyl)-5,7-dimethoxyquinazolin-Active 4(3H)-one2-(3,5-dimethyl-4-(4-(pyrrolidin-1-yl)butoxy)phenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-8-methoxyquinazolin-Active 4(3H)-one3-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6- Activedimethylphenoxy)ethyl)-5-phenylimidazolidine-2,4-dione3-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)benzyl)imidazolidine-Active 2,4-dione2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-6-methoxyquinazolin-Active 4(3H)-one2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7- Activedimethoxypyrido[2,3-d]pyrimidin-4(3H)-one2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-7-fluoro-5-(pyrrolidin-1-Active yl)quinazolin-4(3H)-one5-chloro-2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-Active 4(3H)-one2-(4-(2-(azepan-1-yl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-Active 4(3H)-one2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-difluoroquinazolin-Active 4(3H)-one2-(4-(2-(azetidin-1-yl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-Active 4(3H)-oneN-(1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6- Activedimethylphenoxy)ethyl)azetidin-3-yl)acetamide2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7- Activediisopropoxyquinazolin-4(3H)-one8-chloro-2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-Active 4(3H)-one2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-dimethylquinazolin-Active 4(3H)-one2-(2-(4-(6,8-dimethoxy-1-oxo-1,2-dihydroisoquinolin-3-yl)-2,6- Activedimethylphenoxy)ethyl)isoindoline-1,3-dione2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7- Activediisopropoxypyrido[2,3-d]pyrimidin-4(3H)-one2-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6- Activedimethylphenoxy)ethyl)isoindoline-1,3-dione(S)-2-(3,5-dimethyl-4-((5-oxopyrrolidin-2-yl)methoxy)phenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one2-(4-((4-isopropylpiperazin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-Active 4(3H)-oneN-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)benzyl)piperidin-4-Active yl)-N-isopropylacetamide2-(4-((4-(isopropylamino)piperidin-1-yl)methyl)phenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one2-(4-((1H-tetrazol-5-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-oneActive 1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-Active dimethylphenoxy)ethyl)pyrrolidine-2,5-dione7-(2-(benzyloxy)ethoxy)-5-methoxy-2-(pyridin-4-yl)quinazolin-4(3H)-oneActive 2-(2,6-dimethylpyridin-4-yl)-5,7-dimethoxyquinazolin-4(3H)-oneActive2-(2,6-dimethylpyridin-4-yl)-5-methoxy-7-(2-methoxyethoxy)quinazolin-Active 4(3H)-one2-(2,6-dimethylpyridin-4-yl)-5,7-bis(2-methoxyethoxy)quinazolin-4(3H)-oneActive 2-(2,6-dimethylpyridin-4-yl)-7-methoxy-5-(2-(pyrrolidin-1- Activeyl)ethoxy)quinazolin-4(3H)-one2-(2,6-dimethylpyridin-4-yl)-6-((4-methylpiperazin-1-yl)methyl)quinazolin-Active 4(3H)-one2-(2,6-dimethylpyridin-4-yl)-5-methoxy-7-(2-phenoxyethoxy)quinazolin-Active 4(3H)-one2-(2,6-dimethylpyridin-4-yl)-7-methoxy-5-(2-phenoxyethoxy)quinazolin-Active 4(3H)-one2-(2,6-dimethylpyridin-4-yl)-7-methoxy-5-(2-methoxyethoxy)quinazolin-Active 4(3H)-one2-(2,6-dimethylpyridin-4-yl)-5-methoxy-7-(2-(pyrrolidin-1- Activeyl)ethoxy)quinazolin-4(3H)-one2-(2,6-dimethylpyridin-4-yl)-7-(2-isopropoxyethoxy)-5-methoxyquinazolin-Active 4(3H)-one2-(2,6-dimethylpyridin-4-yl)-5,7-bis(2-isopropoxyethoxy)quinazolin-4(3H)-Active one;7-(2-(benzyloxy)ethoxy)-2-(2,6-dimethylpyridin-4-yl)-5-methoxyquinazolin-Active 4(3H)-one2-(2,6-dimethylpyridin-4-yl)-6-(2-morpholinoethyl)quinazolin-4(3H)-oneActive 2-(2-methylpyridin-4-yl)-6-(morpholinomethyl)quinazolin-4(3H)-oneActive5-methoxy-7-(2-methoxyethoxy)-2-(2-methylpyridin-4-yl)quinazolin-4(3H)-Active one2-(2,6-dimethylpyridin-4-yl)-6-(2-(pyrrolidin-1-yl)ethyl)quinazolin-4(3H)-oneActive2-(2,6-dimethylpyridin-4-yl)-7-(2-methoxyethoxy)-5-(2-(pyrrolidin-1-Active yl)ethoxy)quinazolin-4(3H)-one2-(3,5-dimethoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one Active2-(3-(2-hydroxyethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one Active2-(3-(2-hydroxyethoxy)-5-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-oneActive5,7-dimethoxy-2-(3-methoxy-5-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-Active 4(3H)-oneN-(2-(3-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-5- Activemethoxyphenoxy)ethyl)acetamide2-(3,5-dimethoxyphenyl)-6-(pyridin-4-ylamino)quinazolin-4(3H)-one Active5,7-dimethoxy-2-(3-methoxyphenyl)quinazolin-4(3H)-one Active

Example 128. Quantification of hVCAM mRNA

In this example, hIL-6 mRNA in tissue culture cells was quantitated tomeasure the transcriptional inhibition of hVCAM when treated with acompound of the invention.

Human umbilical vein endothelial cells (HUVECs) were plated in a 96-wellplate (4.0×10³ cells/well) in 100 μL EGM media and incubated for 24 hprior to the addition of the compound of interest. The cells werepretreated for 1 h with the test compound prior to stimulation withtumor necrosis factor-α. The cells were incubated for an additional 24 hbefore the cells were harvested. At time of harvest, the spent media wasremoved from the HUVECs and rinsed in 200 μL PBS. Cell lysis solution(70 μL) was then added the cells in each well and incubated for ˜5-10min at room temperature, to allow for complete cell lysis anddetachment. mRNA was then prepared using the “mRNA Catcher PLUS plate”(Invitrogen), according to the protocol supplied. After the last wash,as much wash buffer as possible was aspirated without allowing the wellsto dry. Elution buffer (E3, 70 μL) was then added to each well. mRNA wasthen eluted by incubating the mRNA Catcher PLUS plate with elutionbuffer for 5 min at 68° C. and then immediately placing the plate onice.

The eluted mRNA so isolated was then used in a one-step quantitativereal-time PCR reaction, using components of the Ultra Sense Kit togetherwith Applied Biosystems primer-probe mixes. Real-time PCR data wasanalyzed, normalizing the Ct values for hVCAM to an internal control,prior to determining the fold induction of each unknown sample, relativeto the control.

In Table 3, an active compound is one that causes a 20% inhibition inVCAM-1 mRNA at a concentration less than or equal to 10 μM.

TABLE 3 Inhibition of VCAM-1 Example expression2-(4-(4-isopropylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-Active one2-(4-(4-acetylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-oneActive 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-oneActiveN-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-Active 4-yl)acetamide2-(4-(4-hexanoylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-Inactive one2-(4-(4-isobutyrylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-Active one2-(4-(4-benzoylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-oneActive2-(4-(4-(4-fluorobenzoyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-Active 4(3H)-oneN-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-Active 4-yl)benzamide2-(4-(4-(5-chloro-1-methyl-1H-pyrazole-4-carbonyl)piperazin-1-yl)phenyl)-Active 5,7-dimethoxyquinazolin-4(3H)-one5,7-dimethoxy-2-(4-(4-(3,3,3-trifluoropropanoyl)piperazin-1- Activeyl)phenyl)quinazolin-4(3H)-one2-(4-(4-(2,5-dichlorothiophene-3-carbonyl)piperazin-1-yl)phenyl)-5,7-Active dimethoxyquinazolin-4(3H)-one2-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)phenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one2-(4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)phenyl)quinazolin-4(3H)-oneInactive2-(4-(4-butylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-oneActive 2-(4-(1,4-diazepan-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-oneActive5,7-dimethoxy-2-(4-(4-methyl-1,4-diazepan-1-yl)phenyl)quinazolin-4(3H)-Active oneN-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-Active 4-yl)-N-ethylacetamide2-(4-((3R,5S)-4-acetyl-3,5-dimethylpiperazin-1-yl)phenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one2-(4-((3R,5S)-3,5-dimethylpiperazin-1-yl)phenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one2-(4-(4-acetyl-3-methylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-Active 4(3H)-one N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-Active yl)phenyl)pyrrolidin-3-yl)acetamide2-(4-(4-isopropylpiperazin-1-yl)phenyl)-8-methoxyquinazolin-4(3H)-oneActive2-(4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-Active 4(3H)-one2-(4-(dimethylamino)naphthalen-1-yl)-6,7-dimethoxyquinazolin-4(3H)-oneActive5,7-dimethoxy-2-(2-(pyrrolidin-1-ylmethyl)-1H-indol-5-yl)quinazolin-4(3H)-Active one5,7-dimethoxy-2-(2-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-5-yl)quinazolin-Active 4(3H)-one2-(2-((dimethylamino)methyl)-1H-indol-5-yl)-5,7-dimethoxyquinazolin-Active 4(3H)-one5,7-dimethoxy-2-(4-(pyridin-3-ylamino)phenyl)quinazolin-4(3H)-one Active2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-5,7-dimethoxyquinazolin-Active 4(3H)-one2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)quinazolin-4(3H)-one Active7-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-2,4-dimethoxy-1,6- Activenaphthyridin-5(6H)-one2-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-Active 4(3H)-one2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one2-(4-(2-(isoindolin-2-yl)ethoxy)-3,5-dimethylphenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-methoxyquinazolin-Active 4(3H)-one 5,7-dichloro-2-(3,5-dimethyl-4-(2-(pyrrolidin-1- Activeyl)ethoxy)phenyl)quinazolin-4(3H)-one2-(4-(2-(4-acetylpiperazin-1-yl)ethoxy)-3,5-dimethylphenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one2-(4-(2-(1H-imidazol-1-yl)ethoxy)-3,5-dimethylphenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-7-methoxyquinazolin-Active 4(3H)-one2-(3,5-dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one2-(3,5-dimethyl-4-(2-(piperidin-1-yl)ethoxy)phenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one5,7-dimethoxy-2-(3-methyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-Active 4(3H)-one3-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6- Activedimethylphenoxy)ethyl)-1-isopropylimidazolidine-2,4-dione2-(3,5-dimethyl-4-(3-(pyrrolidin-1-yl)propyl)phenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one2-(3,5-dimethyl-4-(4-(pyrrolidin-1-yl)butoxy)phenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-8-methoxyquinazolin-Active 4(3H)-one3-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6- Activedimethylphenoxy)ethyl)-5-phenylimidazolidine-2,4-dione3-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2- Activeyl)benzyl)imidazolidine-2,4-dione2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-6-methoxyquinazolin-Active 4(3H)-one2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7- Activedimethoxypyrido[2,3-d]pyrimidin-4(3H)-one2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-7-fluoro-5-(pyrrolidin-Active 1-yl)quinazolin-4(3H)-one5-chloro-2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)quinazolin-Active 4(3H)-one 2-(4-(2-(azepan-1-yl)ethoxy)-3,5-dimethylphenyl)-5,7-Active dimethoxyquinazolin-4(3H)-one2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-difluoroquinazolin-Active 4(3H)-one2-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6- Activedimethylphenoxy)ethyl)isoindoline-1,3-dione(S)-2-(3,5-dimethyl-4-((5-oxopyrrolidin-2-yl)methoxy)phenyl)-5,7- Activedimethoxyquinazolin-4(3H)-one1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6- Activedimethylphenoxy)ethyl)pyrrolidine-2,5-dione7-(2-(benzyloxy)ethoxy)-5-methoxy-2-(pyridin-4-yl)quinazolin-4(3H)-oneActive2-(2,6-dimethylpyridin-4-yl)-5,7-bis(2-methoxyethoxy)quinazolin-4(3H)-Active one 2-(2,6-dimethylpyridin-4-yl)-7-methoxy-5-(2-(pyrrolidin-1-Active yl)ethoxy)quinazolin-4(3H)-one2-(2,6-dimethylpyridin-4-yl)-5-methoxy-7-(2-phenoxyethoxy)quinazolin-Active 4(3H)-one2-(2,6-dimethylpyridin-4-yl)-7-methoxy-5-(2-phenoxyethoxy)quinazolin-Active 4(3H)-one2-(2,6-dimethylpyridin-4-yl)-7-methoxy-5-(2-methoxyethoxy)quinazolin-Inactive 4(3H)-one2-(2,6-dimethylpyridin-4-yl)-5-methoxy-7-(2-(pyrrolidin-1- Inactiveyl)ethoxy)quinazolin-4(3H)-one2-(2,6-dimethylpyridin-4-yl)-7-(2-isopropoxyethoxy)-5-methoxyquinazolin-Active 4(3H)-one2-(2,6-dimethylpyridin-4-yl)-5,7-bis(2-isopropoxyethoxy)quinazolin-4(3H)-Active one;7-(2-(benzyloxy)ethoxy)-2-(2,6-dimethylpyridin-4-yl)-5-methoxyquinazolin-Active 4(3H)-one2-(2,6-dimethylpyridin-4-yl)-6-(2-morpholinoethyl)quinazolin-4(3H)-oneInactive2-(2-methylpyridin-4-yl)-6-(morpholinomethyl)quinazolin-4(3H)-oneInactive5-methoxy-7-(2-methoxyethoxy)-2-(2-methylpyridin-4-yl)quinazolin-4(3H)-Active one2-(2,6-dimethylpyridin-4-yl)-6-(2-(pyrrolidin-1-yl)ethyl)quinazolin-4(3H)-Active one2-(2,6-dimethylpyridin-4-yl)-7-(2-methoxyethoxy)-5-(2-(pyrrolidin-1-Active yl)ethoxy)quinazolin-4(3H)-one2-(3,5-dimethoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one Active2-(3-(2-hydroxyethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one Active2-(3-(2-hydroxyethoxy)-5-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-Active one 5,7-dimethoxy-2-(3-methoxy-5-(2-(pyrrolidin-1- Activeyl)ethoxy)phenyl)quinazolin-4(3H)-oneN-(2-(3-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-5- Activemethoxyphenoxy)ethyl)acetamide2-(3,5-dimethoxyphenyl)-6-(pyridin-4-ylamino)quinazolin-4(3H)-oneInactive 5,7-dimethoxy-2-(3-methoxyphenyl)quinazolin-4(3H)-one Active

What is claimed is:
 1. A method for reducing IL-6 and/or VCAM-1 in asubject, comprising administering a therapeutically effective amount ofat least one compound of Formula I:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, orhydrate thereof, wherein: Q and V are independently selected from CH andnitrogen; U is selected from C═O and SO₂; Rc is selected from hydrogen,C₁-C₆ alkyl, and C₃-C₆ cycloalkyl; Ra₁, Ra₂, and Ra₃ are independentlyselected from hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆alkoxy, halogen, amino, amide, hydroxyl, heterocycle, and C₃-C₆cycloalkyl, wherein Ra₁ and Ra₂ and/or Ra₂ and Ra₃ may be connected toform a cycloalkyl or a heterocycle; Rb₂ and Rb₆ are independentlyselected from hydrogen, halogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₆cycloalkyl, hydroxyl, and amino; Rb₃ and Rb₅ are independently selectedfrom hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl,hydroxyl, and amino, wherein Rb₂ and Rb₃ and/or Rb₅ and Rb₆ may beconnected to form a cycloalkyl or a heterocycle;

represents a 3-8 membered ring system wherein: W is selected from carbonand nitrogen; Z is selected from CR₆R₇, NR₈, oxygen, sulfur, —S(O)—, and—SO₂—; said ring system being optionally fused to another ring selectedfrom cycloalkyl, heterocycle, and phenyl, and wherein said ring systemis optionally selected from rings having the structures

R₃, R₄, and R₅ are independently selected from hydrogen, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, aryl,aryloxy, hydroxyl, amino, amide, oxo, —CN, and sulfonamide; R₆ and R₇are independently selected from hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, aryl, halogen, hydroxyl, acyl, and —CN;and R₈ is selected from hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, acyl, and C₃-C₆ cycloalkyl; and R₉, R₁₀, R₁₁, and R₁₂ areindependently selected from hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, aryl, hydroxyl, sulfonyl, and acyl, providedthat if Q=CH, then at least one of Ra₁, Ra₂, and Ra₃ is not hydrogen; ifZ═NAc, then only one of Ra₁, Ra₂, and Ra₃ is hydrogen, and Ra₁ is not—OCH₂CH₂OMe; if Ra₁ and Ra₃ are both OMe, then R₈ is not —C(O)CH₂OH; andfurther provided that the compound of Formula I is not5,7-dimethoxy-2-(4-morpholinophenyl)quinazolin-4(3H)-one,5,7-dimethoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one,or2-(4-(1-cyclopentylpiperidin-4-yl)phenyl)-3-methylquinazolin-4(3H)-one.2. The method according to claim 1, wherein

R₃ and R₄ are independently selected from hydrogen, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, aryloxy, aryl,hydroxyl, amino, amide, oxo, —CN, and sulfonamide; and R₈ is selectedfrom hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, acyl, C₃-C₈ cycloalkyl, andC₂-C₆ alkynyl.
 3. The method according to claim 1, wherein

R₃ and R₄ are independently selected from hydrogen, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, aryloxy, aryl,hydroxyl, amino, amide, oxo, —CN, and sulfonamide; and R₉ and R₁₀ areindependently selected from hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, aryl, heterocycle, sulfonyl, carbamate,carboxamide, and acyl.
 4. The method according to claim 1, wherein

R₃ and R₄ are independently selected from hydrogen, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, aryloxy, aryl,hydroxyl, amino, amido, oxo, —CN, and sulfonamide; and R₈ is selectedfrom hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, acyl, andC₃-C₆ cycloalkyl.
 5. The method according to claim 1, wherein U is C═O;Rc is hydrogen; Ra₂ is hydrogen; Ra₁ and Ra₃ are independently selectedfrom C₁-C₆ alkoxy, hydrogen, and halogen; Rb₂, Rb₃, Rb₅, and Rb₆ areeach hydrogen;

is selected from

R₃ and R₄ are independently selected from hydrogen and C₁-C₆ alkyl; R₅is selected from C₁-C₆ alkyl and hydrogen; and R₉, R₁₀, R₁₁, and R₁₂ areindependently selected from C₁-C₆ alkyl, hydrogen, acyl, and sulfonyl.6. The method according to claim 1, wherein U is C═O; Rc is hydrogen;Ra₂ is hydrogen; Ra₁ and Ra₃ are independently selected from methoxy,hydrogen, and halogen; Rb₂, Rb₃, Rb₅, and Rb₆ are each hydrogen;

is selected from

R₃ and R₄ are independently selected from hydrogen and methyl; R₈ isselected from hydrogen, hydroxyethyl, butyl, acetyl, isopropyl,4-hexanoyl, 4-isobutyryl, benzoyl, 4-fluorobenzoyl, 4-picolinoyl,4-nicotinoyl, 4-isonicotinoyl, thiophene-2-carbonyl,5-chloro-1-methyl-1H-pyrazole-4-carbonyl, 3,3,3-trifluoropropanoyl,2,5-dichlorothiopene-3-carbonyl, cyclopropanecarbonyl, 4-fluorobenzyl,benzyl, 2,2,2-trifluoroethyl, tertbutoxycarbonyl, and formyl; R₉ and R₁₀are independently selected from hydrogen, methyl, cyclopropylmethyl, andacetyl; and R₁₁ and R₁₂ are independently selected from hydrogen,acetyl, methanesulfonyl, dimethylaminocarbonyl, benzoyl, benzyl, ethyl,and isopropyl.
 7. A method for reducing IL-6 and/or VCAM-1 in a subject,comprising administering a therapeutically effective amount of at leastone compound selected from:2-(4-((3R,5S)-4-acetyl-3,5-dimethylpiperazin-1-yl)phenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one;2-(4-(4-hydroxypiperidin-1-yl)phenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one;2-(4-((3R,5S)-4-acetyl-3,5-dimethylpiperazin-1-yl)phenyl)-5-methoxy-7-(2-methoxyethoxy)quinazolin-4(3H)-one;2-(4-(4-isopropylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(4-acetylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one;N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)acetamide;N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)methanesulfonamide;3-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)-1,1-dimethylurea;2-(4-(4-hexanoylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(4-isobutyrylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(4-benzoylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(4-(4-fluorobenzoyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)benzamide;5,7-dimethoxy-2-(4-(4-picolinoylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one;5,7-dimethoxy-2-(4-(4-nicotinoylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one;2-(4-(4-isonicotinoylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;5,7-dimethoxy-2-(4-(4-(thiophene-2-carbonyl)piperazin-1-yl)phenyl)quinazolin-4(3H)-one;2-(4-(4-(5-chloro-1-methyl-1H-pyrazole-4-carbonyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;5,7-dimethoxy-2-(4-(4-(3,3,3-trifluoropropanoyl)piperazin-1-yl)phenyl)quinazolin-4(3H)-one;2-(4-(4-(2,5-dichlorothiophene-3-carbonyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(4-(4-fluorobenzyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(4-benzylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)phenyl)quinazolin-4(3H)-one;2-(4-(4-butylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(4-acetyl-1,4-diazepan-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(1,4-diazepan-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;5,7-dimethoxy-2-(4-(4-methyl-1,4-diazepan-1-yl)phenyl)quinazolin-4(3H)-one;N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)-N-ethylacetamide;2-(4-((3R,5S)-4-acetyl-3,5-dimethylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(3R,5S)-3,5-dimethylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(4-acetyl-3-methylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)pyrrolidin-3-yl)acetamide;2-(4-(4-isopropylpiperazin-1-yl)phenyl)-8-methoxyquinazolin-4(3H)-one;2-(4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)-N-isopropylacetamide;5-chloro-2-(4-(4-isopropylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one;2-(4-(3R,5S)-4-isopropyl-3,5-dimethylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;5,7-dimethoxy-2-(4-(piperidin-4-yl)phenyl)quinazolin-4(3H)-one;5,7-dimethoxy-2-(4-(3-(methylamino)pyrrolidin-1-yl)phenyl)quinazolin-4(3H)-one;tert-butyl4-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidine-1-carboxylate;N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)pyrrolidin-3-yl)-N-methylacetamide;2-(4-(4-(isopropylamino)piperidin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(1-acetylpiperidin-4-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;5,7-dimethoxy-2-(4-(3-methylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one;N-benzyl-N-(1-(5-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperidin-4-yl)acetamide;2-(6-(4-(benzylamino)piperidin-1-yl)pyridin-3-yl)-5,7-dimethoxyquinazolin-4(3H)-one;4-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperazine-1-carbaldehyde:2-(4-(2-O-acetylazetidin-3-yl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(3-(cyclopropylmethylamino)pyrrolidin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;5,7-dimethoxy-2-(4-(4-oxopiperidin-1-yl)phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one;and pharmaceutically acceptable salts and hydrates thereof.
 8. Themethod according to claim 1, wherein the therapeutically effectiveamount of the compound is administered with at least onepharmaceutically acceptable carrier in a pharmaceutically acceptablecomposition.
 9. The method according to claim 1, further comprisingtreating and/or reducing the risk of acquiring cardiovascular disorders,inflammatory diseases, and/or cancer, characterized by alteredexpression of IL-6 and/or VCAM-1 proliferation.
 10. The method accordingto claim 9, wherein the subject is a human.
 11. A compound of Formula I:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, orhydrate thereof, wherein: Q is selected from CH and nitrogen; V isnitrogen; U is selected from C═O and SO₂; Rc is selected from hydrogen,C₁-C₆ alkyl, and C₃-C₆ cycloalkyl; Ra₁ and Ra₃ are independentlyselected from hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆alkoxy, halogen, amino, amide, hydroxyl, heterocycle, and C₃-C₆cycloalkyl; Ra₂ is hydrogen or Ra₁ and Ra₂ and/or Ra₂ and Ra₃ may beconnected to form a cycloalkyl or a heterocycle; Rb₂ and Rb₆ areindependently selected from hydrogen, halogen, C₁-C₆ alkyl, C₂-C₆alkenyl, C₃-C₆ cycloalkyl, hydroxyl, and amino; Rb₃ and Rb₅ areindependently selected from hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, C₃-C₆ cycloalkyl, hydroxyl, and amino, wherein Rb₂ and Rb₃and/or Rb₅ and Rb₆ may be connected to form a cycloalkyl or aheterocycle;

represents a 3-8 membered ring system wherein: W is selected from carbonand nitrogen; Z is selected from CR₆R₇, NR₈, oxygen, sulfur, —S(O)—, and—SO₂—; said ring system being optionally fused to another ring selectedfrom cycloalkyl, heterocycle, and phenyl, and wherein said ring systemis optionally selected from rings having the structures

R₃, R₄, and R₅ are independently selected from hydrogen, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, aryl,aryloxy, hydroxyl, amino, amide, oxo, —CN, and sulfonamide; R₆ and R₇are independently selected from hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, aryl, halogen, hydroxyl, acyl, and —CN;R₈ is selected from hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl;C₃-C₆ cycloalkyl, and acyl; and R₉, R₁₀, R₁₁, and R₁₂ are independentlyselected from hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, aryl, hydroxyl, sulfonyl, and acyl, provided that if Q=CH,then at least one of Ra₁ and Ra₃ is not hydrogen; if Z═NAc, then onlyone of Ra₁, Ra₂, and Ra₃ is hydrogen, and Ra₁ is not —OCH₂CH₂OMe; if Ra₁and Ra₃ are both OMe, than R₈ is not —C(O)CH₂OH; and further providedthat the compound of Formula I is not5,7-dimethoxy-2-(4-morpholinophenyl)quinazolin-4(3H)-one,5,7-dimethoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one,or2-(4-(1-cyclopentylpiperidin-4-yl)phenyl)-3-methylquinazolin-4(3H)-one.12. The compound according to claim 11, wherein

R₃ and R₄ are independently selected from hydrogen, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, aryloxy, aryl,hydroxyl, amino, amide, oxo, —CN, and sulfonamide; and R₈ is selectedfrom hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, acyl, andC₃-C₆ cycloalkyl.
 13. The compound according to claim 11, wherein

R₃ and R₄ are independently selected from hydrogen, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, aryloxy, aryl,hydroxyl, amino, amide, oxo, —CN, and sulfonamide; and R₉ and R₁₀ areindependently selected from hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, aryl, heterocycle, sulfonyl, carbamate,carboxamide, and acyl.
 14. The compound according to claim 11, wherein

R₃ and R₄ are independently selected from hydrogen, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, aryloxy, aryl,hydroxyl, amino, amide, oxo, —CN, and sulfonamide; and R₉ and R₁₀ areindependently selected from hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, aryl, heterocycle, sulfonyl, carbamate,carboxamide, and acyl.
 15. The compound according to claim 11, wherein

R₃ and R₄ are independently selected from hydrogen, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, aryloxy, aryl,hydroxyl, amino, amide, oxo, —CN, and sulfonamide; and R₈ is selectedfrom hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, acyl, andC₃-C₆ cycloalkyl.
 16. The compound according to claim 11, wherein U isC═O Rc is hydrogen; Ra₂ is hydrogen; Ra₁ and Ra₃ are independentlyselected from C₁-C₆ alkoxy, hydrogen, and halogen; Rb₂, Rb₃, Rb₅, andRb₆ are each hydrogen;

is selected from

R₃ and R₄ are independently selected from hydrogen and C₁-C₆ alkyl; R₈is selected from C₁-C₆ alkyl, and hydrogen; and R₉, R₁₀, R₁₁, and R₁₂are independently selected from C₁-C₆ alkyl, hydrogen, acyl, andsulfonyl.
 17. The compound according to claim 11, wherein U is C═O Rc ishydrogen; Ra₂ is hydrogen; Ra₁ and Ra₃ are independently selected frommethoxy, hydrogen, and halogen; Rb₂, Rb₃, Rb₅, and Rb₆ are eachhydrogen;

is selected from

R₃ and R₄ are independently selected from hydrogen and methyl; R₈ isselected from hydrogen, hydroxyethyl, butyl, acetyl, isopropyl,4-hexanoyl, 4-isobutyryl, benzoyl, 4-fluorobenzoyl, 4-picolinoyl,4-nicotinoyl, 4-isonicotinoyl, thiophene-2-carbonyl,5-chloro-1-methyl-1H-pyrazole-4-carbonyl, 3,3,3-trifluoropropanoyl,2,5-dichlorothiopene-3-carbonyl, cyclopropanecarbonyl, 4-fluorobenzyl,benzyl, 2,2,2-trifluoroethyl, tertbutoxycarbonyl, and formyl; and R₉ andR₁₀ are independently selected from hydrogen, methyl, cyclopropylmethyl,and acetyl; and R₁₁ and R₁₂ are independently selected from hydrogen,acetyl, methanesulfonyl, dimethylaminocarbonyl, benzoyl, benzyl, ethyl,and isopropyl.
 18. A compound selected from:2-(4-((3R,5S)-4-acetyl-3,5-dimethylpiperazin-1-yl)phenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one;2-(4-(4-hydroxypiperidin-1-yl)phenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one;2-(4-((3R,5S)-4-acetyl-3,5-dimethylpiperazin-1-yl)phenyl)-5-methoxy-7-(2-methoxyethoxy)quinazolin-4(3H)-one;2-(4-(4-acetylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one;N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)acetamide;N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)methanesulfonamide3-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)-1,1-dimethylurea;2-(4-(4-hexanoylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(4-isobutyrylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(4-benzoylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(4-(4-fluorobenzoyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)benzamide;5,7-dimethoxy-2-(4-(4-picolinoylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one;5,7-dimethoxy-2-(4-(4-nicotinoylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one;2-(4-(4-isonicotinoylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;5,7-dimethoxy-2-(4-(4-(thiophene-2-carbonyl)piperazin-1-yl)phenyl)quinazolin-4(3H)-one;2-(4-(4-(5-chloro-1-methyl-1H-pyrazole-4-carbonyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;5,7-dimethoxy-2-(4-(4-(3,3,3-trifluoropropanoyl)piperazin-1-yl)phenyl)quinazolin-4(3H)-one;2-(4-(4-(2,5-dichlorothiophene-3-carbonyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(4-(cyclopropanecarbonyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(4-(4-fluorobenzyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(4-benzylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)phenyl)quinazolin-4(3H)-one;2-(4-(4-acetyl-1,4-diazepan-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(1,4-diazepan-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;5,7-dimethoxy-2-(4-(4-methyl-1,4-diazepan-1-yl)phenyl)quinazolin-4(3H)-one;N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)-N-ethylacetamide;2-(4-((3R,5S)-4-acetyl-3,5-dimethylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-((3R,5S)-3,5-dimethylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(4-acetyl-3-methylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)pyrrolidin-3-yl)acetamide;2-(4-(4-isopropylpiperazin-1-yl)phenyl)-8-methoxyquinazolin-4(3H)-one;2-(4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4Hone;N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidin-4-yl)-N-isopropylacetamide;5-chloro-2-(4-(4-isopropylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one;2-(4-((3R,5S)-4-isopropyl-3,5-dimethylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;5,7-dimethoxy-2-(4-(piperidin-4-yl)phenyl)quinazolin-4(3H)-one;5,7-dimethoxy-2-(4-(3-(methylamino)pyrrolidin-1-yl)phenyl)quinazolin-4(3H)-one;tert-butyl4-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperidine-1-carboxylate;N-(1-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)pyrrolidin-3-yl)-N-methylacetamide;2-(4-(4-(isopropylamino)piperidin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(1-acetylpiperidin-4-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;5,7-dimethoxy-2-(4-(3-methylpiperazin-1H)phenyl)quinazolin-4(3H)-one;N-benzyl-N-(1-(5-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperidin-4-0)acetamide;2-(6-(4-(benzylamino)piperidin-1-yl)pyridin-3-yl)-5,7-dimethoxyquinazolin-4H)-one;4-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)piperazine-1-carbaldehyde;2-(4-(2-(1-acetylazetidin-3-yl)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(3-(cyclopropylmethylamino)pyrrolidin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;5,7-dimethoxy-2-(4-(4-oxopiperidin-1-yl)phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one;and pharmaceutically acceptable salts and hydrates thereof.
 19. Apharmaceutical composition comprising a compound of claim 11 and apharmaceutically acceptable carrier.
 20. A method for reducing IL-6and/or VCAM-1 in a subject, comprising administering a compositionaccording to claim
 19. 21. The method according to claim 20, furthercomprising treating and/or reducing the risk of acquiring cardiovasculardisorders, and inflammatory diseases, and/or cancer, characterized byaltered expression of IL-6 and/or VCAM-1 proliferation.
 22. The methodaccording to claim 21, wherein the subject is a human.
 23. The methodaccording to claim 9, wherein the inflammatory disease is selected fromarthritis, rheumatoid arthritis, asthma, dermatitis, psoriasis, cysticfibrosis, post transplantation late and chronic solid organ rejection,multiple sclerosis, systemic lupus erythematosus, inflammatory boweldiseases, autoimmune diabetes, diabetic retinopathy, diabeticnephropathy, diabetic vasculopathy, ocular inflammation, uveitis,rhinitis, ischemic-reperfusion injury, post-angioplasty restenosis,chronic obstructive pulmonary disease (COPD), glomerulonephritis,Grave's disease, gastrointestinal allergies, and conjunctivitis.
 24. Themethod according to claim 9, wherein the cancer is selected frommultiple myeloma, lymphoma, leukemia, solid tumors, prostate and bladdercancers, cardiac myxoma, cerebral edema secondary to brain tumors,hormone-independent prostate cancer, B cell lymphoma, AIDS-associatedlymphoma, and metastatic renal cell carcinoma.
 25. The method accordingto claim 21, wherein the inflammatory disease is selected fromarthritis, rheumatoid arthritis, asthma, dermatitis, psoriasis, cysticfibrosis, post transplantation late and chronic solid organ rejection,multiple sclerosis, systemic lupus erythematosus, inflammatory boweldiseases, autoimmune diabetes, diabetic retinopathy, diabeticnephropathy, diabetic vasculopathy, ocular inflammation, uveitis,rhinitis, ischemic-reperfusion injury, post-angioplasty restenosis,chronic obstructive pulmonary disease (COPD), glomerulonephritis,Grave's disease, gastrointestinal allergies, and conjunctivitis.
 26. Themethod according to claim 21, wherein the cancer is selected frommultiple myeloma, lymphoma, leukemia, solid tumors, prostate and bladdercancers, cardiac myxoma, cerebral edema secondary to brain tumors,hormone-independent prostate cancer, B cell lymphoma, AIDS-associatedlymphoma, and metastatic renal cell carcinoma.
 27. A pharmaceuticalcomposition comprising a compound of claim 7 and a pharmaceuticallyacceptable carrier.
 28. A method for treating and/or reducing, the riskof acquiring cardiovascular disorders, inflammatory diseases, and/orcancer, characterized by altered expression of IL-6 and/or VCAM-1proliferation, comprising administering a composition according to claim27.
 29. The method according to claim 28, wherein the subject is ahuman.
 30. The method according to claim 28, wherein the inflammatorydisease is selected from arthritis, rheumatoid arthritis, asthma,dermatitis, psoriasis, cystic fibrosis, post transplantation late andchronic solid organ rejection, multiple sclerosis, systemic lupuserythematosus, inflammatory bowel diseases, autoimmune diabetes,diabetic retinopathy, diabetic nephropathy, diabetic vasculopathy,ocular inflammation, uveitis, rhinitis, ischemic-reperfusion injury,post-angioplasty restenosis, chronic obstructive pulmonary disease(COPD), glomerulonephritis, Grave's disease, gastrointestinal allergies,and conjunctivitis.
 31. The method according to claim 28, wherein thecancer is selected from multiple myeloma, lymphoma, leukemia, solidtumors, prostate and bladder cancers, cardiac myxoma, cerebral edemasecondary to brain tumors, hormone-independent prostate cancer, B celllymphoma, AIDS-associated lymphoma, and metastatic renal cell carcinoma.32. A pharmaceutical composition comprising a compound of claim 18 and apharmaceutically acceptable carrier.
 33. A method for reducing IL-6and/or VCAM-1 in a subject, comprising administering a compositionaccording to claim
 32. 34. The method according to claim 33, furthercomprising treating and/or reducing the risk of acquiring cardiovasculardisorders, inflammatory diseases, and/or cancer, characterized byaltered expression of IL-6 and/or VCAM-1 proliferation.
 35. The methodaccording to claim 34, wherein the subject is a human.
 36. The methodaccording to claim 34, wherein the inflammatory disease is selected fromarthritis, rheumatoid arthritis, asthma, dermatitis, psoriasis, cysticfibrosis, post transplantation late and chronic solid organ rejection,multiple sclerosis, systemic lupus erythematosus, inflammatory boweldiseases, autoimmune diabetes, diabetic retinopathy, diabeticnephropathy, diabetic vasculopathy, ocular inflammation, uveitis,rhinitis, ischemia-reperfusion injury, post-angioplasty restenosis,chronic obstructive pulmonary disease (COPD), glomerulonephritis,Grave's disease, gastrointestinal allergies, and conjunctivitis.
 37. Themethod according to claim 34, wherein the cancer is selected frommultiple myeloma, lymphoma, leukemia, solid tumors, prostate and bladdercancers, cardiac myxoma, cerebral edema secondary to brain tumors,hormone-independent prostate cancer, B cell lymphoma, AIDS-associatedlymphoma, and metastatic renal cell carcinoma.
 38. The method accordingto claim 7, wherein the compound is selected from:5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one;2-(4-(4-acetyl-3-methylpiperazin-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;and pharmaceutically acceptable salts and hydrates thereof.
 39. Thecompound according to claim 18, wherein the compound is selected from:5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one;2-(4-(4-acetyl-3-methylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;and pharmaceutically acceptable salts and hydrates thereof.